Pyrrolotriazine compounds as kinase inhibitors

ABSTRACT

The present invention provides compounds of formula I  
                 
and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4 thereby making them useful as antiproliferative agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.

This application is a continuation of Ser. No. 11/019,901 filed on Dec.22, 2004, which claims the priority benefit of U.S. ProvisionalApplication No. 60/533,335 filed Dec. 29, 2003, the disclosures of whichare incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compounds that inhibit the tyrosine kinaseactivity of growth factor receptors such as HER1, HER2, and HER4 therebymaking them useful as anti-cancer agents. The compounds are also usefulin the treatment of diseases, other than cancer, which are associatedwith signal transduction pathways operating through growth factorreceptors such as HER1, HER2 and HER4.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain.

The human epidermal growth factor receptor (HER) family consists of fourdistinct receptor tyrosine kinases referred to HER1, HER2, HER3, andHER4. These kinases are also referred to as erbB1, erbB2, etc. HER1 isalso commonly referred to as the epidermal growth factor (EGF) receptor.With the exception of HER3, these receptors have intrinsic proteinkinase activity that is specific for tyrosine residues ofphosphoacceptor proteins. The HER kinases are expressed in mostepithelial cells as well as tumor cells of epithelial origin. They arealso often expressed in tumor cells of mesenchymal origin such assarcomas or rhabdomyosarcomas. RTKs such as HER1 and HER2 are involvedin cell proliferation and are associated with diseases such as psoriasisand cancer. Disruption of signal transduction by inhibition of thesekinases would have an antiproliferative and therapeutic effect.

The enzymatic activity of receptor tyrosine kinases can be stimulated byeither overexpression, or by ligand-mediated dimerization. The formationof homodimers as well as heterodimers has been demonstrated for the HERreceptor family. An example of homodimerization is the dimerization ofHER1 (EGF receptor) by one of the EGF family of ligands (which includesEGF, transforming growth factor alpha, betacellulin, heparin-bindingEGF, and epiregulin). Heterodimerization among the four HER receptorkinases can be promoted by binding to members of the heregulin (alsoreferred to neuregulin) family of ligands. Such heterodimerization asinvolving HER2 and HER3, or a HER3/HER4 combination, results in asignificant stimulation of the tyrosine kinase activity of the receptordimers even though one of the receptors (HER3) is enzymatically inert.The kinase activity of HER2 has been shown to be activated also byvirtue of overexpression of the receptor alone in a variety of celltypes. Activation of receptor homodimers and heterodimers results inphosphorylation of tyrosine residues on the receptors and on otherintracellular proteins. This is followed by the activation ofintracellular signaling pathways such as those involving the microtubuleassociated protein kinase (MAP kinase) and the phosphatidylinositol3-kinase (PI3 kinase). Activation of these pathways have been shown tolead to cell proliferation and the inhibition of apoptosis. Inhibitionof HER kinase signaling has been shown to inhibit cell proliferation andsurvival.

All protein kinases contain a structurally conserved catalytic domain ofapproximately 250-300 amino acid residues¹. FIG. 1 shows an X-raystructure of HER1² which encompasses the highly conserved features ofall members of the protein kinase family. The protein kinase fold isseparated into two subdomains, or lobes. The smaller N-terminal lobe, orN lobe, is composed of a five-stranded β sheet and one prominent αhelix, called helix αC. The C lobe is larger and is predominantlyhelical. The two lobes are connected through a single polypeptide strand(the linker/hinge region), which acts as a hinge about which the twodomains can rotate with respect to one other upon binding of ATP and/orsubstrate. ATP is bound in the deep cleft between the two lobes and sitsbeneath a highly conserved loop connecting strands β1 and β2. Thisphosphate binding loop, or P loop, contains a conserved glycine-richsequence motif (GXGXφG) where φ is usually tyrosine or phenylalanine.The glycine residues allow the loop to approach the phosphates of ATPvery closely and to coordinate them via backbone interactions. Theconserved aromatic side chain caps the site of phosphate transfer. ATPis anchored to the enzyme via hydrogen bonds between its adenine moietyand the backbone atoms of the linker region, and the ribose ring toresidues at the start of the C-terminal domain.

Optimal phosphotransfer requires the precise spatial arrangement ofseveral catalytic residues that are absolutely conserved among all knownkinases. Asp813 and Asn818 (HER1 numbering as given in reference 2 ornumbered as Asp837 and Asn842 as found in REFSEQ: accessionNM_(—)005228) emanate from a highly conserved loop structure at the baseof the active site, called the catalytic loop. Asp813 interacts with theattacking hydroxyl side chain of the substrate, while Asn818 engages inhydrogen bonding interactions that orient Asp813. Asn818 and anotherabsolutely conserved catalytic residue, Asp831 (numbered as Asp855 asfound in REFSEQ: accession NM_(—)005228), are also required for thebinding of two divalent metal cations involved in coordination of thetriphosphate group.

Numerous structures of complexes with ATP, its analogs, orsmall-molecule inhibitors bound to different protein kinases haveprovided a clear description of the organization of the catalytic domainand the ATP-binding cleft and of the similarities and differences thatexist within the binding region³. It is now clear that there are regionswithin the binding cleft that are not occupied by ATP, and that theseshow structural diversity between members of the kinase family. FIG. 2shows the interactions of ATP with the hinge region of humancyclin-dependent kinase 2 (CDK2)⁴. The generic regions of all knownkinase ATP binding sites are delineated in the figure as: (1) theadenine binding region; (2) the ribose pocket; (3) the phosphate bindingpocket; (4) a mostly hydrophobic region 1, behind the adenine ring, and(5) region 2, a cleft or a tunnel adjacent to the ribose pocket and theN3 nitrogen of adenine which points towards a surface-exposed area ofthe kinase domain. The available structures of kinase/inhibitorcomplexes indicate that one can take advantage of the regions notoccupied by ATP, e.g. regions 1 and 2, for increasing bindinginteractions and hence binding potency and potentially because ofsequence differences between kinases in these regions also modulateselectivity.

A combination of crystallography, modeling, screening and medicinalchemistry efforts has led to the understanding of the binding mode ofthe pyrrolotriazine chemotype in the ATP binding site. Based on an X-raycrystal structure of the pyrrolotriazine chemotype inhibitor in VEGFR-2,it has been shown that the pyrrolotriazine ring binds in the adeninepocket and makes several key interactions with the hinge regionsimilarly to ATP. In this binding mode, the C5 group is directed intothe highly conserved ribose-phosphate pockets. The C4 group, dependingon its chemical constituency, can be directed into the specificityregion 1 and the C6 group is directed into the specificity region 2.Modeling of enumerated examples of this chemotype in HER1 shows that theC5 group claimed in this invention can at the least occupy theribose-phosphate pocket and interact with at least one or more of theabsolutely conserved residues involved in phosphate binding, e.g.,Asn818 and Asp831 (HER1 numbering).

The conserved nature of the kinase catalytic core structure makes it anexcellent target for the generic kinase inhibitor template afforded bythe pyrrolotriazine ring and the C5 group. This template can besuccessfully derivatized to make specific and potent kinaseATP-competitive inhibitors by targeting the poorly conserved areas ofthe ATP-binding site.

It has surprisingly been found that compounds of the invention and othercompounds such as those disclosed in U.S. Pat. Nos. 5,457,105, 5,616,582and 5,770,599, which contain a small aniline derivative as thesubstituent off of the C4 position of the bicyclic ring, exhibit bothHER1 and HER2 activity.

REFERENCES

-   (1) S. K. Hanks and T. Hunter, Protein kinases 6. The eukaryotic    protein kinase superfamily: kinase (catalytic) domain structure and    classification. FASEB J. 9 (1995), pp. 576-596.-   (2) PDB ID: 1M14-   Stamos, J., Sliwkowski, M. X., Eigenbrot, C.: Structure of the    Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex    with a 4-Anilinoquinazoline Inhibitor. J. Biol. Chem. 277 pp. 46265    (2002).-   (3) H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N.    Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourne. The Protein Data    Bank. Nucleic Acids Research, 28 pp. 235-242 (2000): website:    http://www.pdb.org/.-   (4) PDB ID: IHCK-   Schulze-Gahmen, U., De Bondt, H. L., Kim, S. H.: High-resolution    crystal structures of human cyclin-dependent kinase 2 with and    without ATP: bound waters and natural ligand as guides for inhibitor    design. J Med Chem 39 pp. 4540 (1996).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the X-ray structure of HER1, color-coded by key elementsof a typical kinase.

FIG. 2 depicts an X-ray structure of CDK2 complexed with ATP. Differentregions of a typical ATP-binding site are delineated.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds.

In accordance with the present invention, there are disclosed compoundsof formula I

wherein the symbols have the following meanings and are, for eachoccurrence, independently selected:

-   -   R¹ is cycloalkyl or substituted cycloalkyl, aryl or substituted        aryl, heterocyclyl or substituted heterocyclyl;    -   R² is aryl, substituted aryl, heteroaryl or substituted        heteroaryl, heterocyclyl or substituted heterocyclyl;    -   R³ is hydrogen, alkyl or substituted alkyl;    -   X is a direct bond, —NR³— or —O—;    -   Y is a direct bond, alkyl or substituted alkyl, alkenyl or        substituted alkenyl, alkynyl or substituted alkynyl;        or a pharmaceutically acceptable salt or stereoisomer thereof,        with the proviso that R² is not indazolyl or substituted        indazolyl.

These compounds inhibit the tyrosine kinase activity of growth factorreceptors such as HER2.

In another embodiment, the invention comprises a compound of formula Iwherein

-   -   R¹ is heterocyclyl or substituted heterocyclyl;    -   R² is aryl, substituted aryl, heteroaryl or substituted        heteroaryl;    -   R³ is hydrogen;    -   X is —NR³— or —O—;    -   Y is alkyl or substituted alkyl;        or a pharmaceutically acceptable salt or stereoisomer thereof.

Preferred R² substituents include

-   -   oxazolyl, thienyl, pyridinyl, thiazolyl, pyrazinyl, and phenyl,        all of which may be suitably substituted with one or more        substitutents.

Preferred R¹ substituents include

-   -   benzyl, imidazolyl-ethyl, (methyl-imidazolyl)-ethyl,        piperidinyl-ethyl, pyridinyl-propyl, pyridinyl-methyl,        morpholinyl-ethyl, (methyl-imidazolyl)-methyl, pyridinyl-ethyl,        amino-piperidinyl-methyl, 4-amino-1-methyl-piperidin-3-ol,        (methyl-piperazinyl)-ethyl, pyridinyl-ethyl,        (methyl-piperidinyl)-ethyl, (methyl-imidazolyl)-propyl,        (methyl-piperidinyl)-methyl, (methyl-piperazinyl)-propyl,        diisopropylamino-ethyl, piperidinyl-propyl, dimethylamino-ethyl,        dimethylamino-propyl, [(trifluoro-acetyl)-piperidinyl]-propyl,        piperidinyl-ethyl, piperazinyl-ethyl, piperazinyl-propyl,        pyrrolidinyl-ethyl, triazolyl-ethyl, triazolyl-propyl,        (dimethylamino-ethoxy)-ethyl, imidazolyl-propyl,        [(trifluoro-acetyl)-piperidinyl]-propyl,        (piperazinyl-ethoxy)-ethyl,        [(trifluoro-acetyl)-piperazinyl]-propyl,        [(trifluoro-acetyl)-piperazinyl]-ethyl, piperidinyl-methyl,        pyrazolyl-ethyl, (amino-ethoxy)-ethyl, (methoxy-ethoxy)-ethyl,        pyrazolyl-propyl, [(methoxy-ethyl)-methyl-amino]-ethyl,        morpholinyl-propyl, (cyanomethyl-piperazinyl)-ethyl,        [(cyano-ethyl)-methyl-amino]-ethyl,        [(methoxy-ethyl)-piperidinyl]-methyl,        [(methoxy-ethyl)-piperidinyl]-ethyl,        [(fluoro-ethyl)-methyl-amino]-ethyl,        [(fluoro-ethyl)-methyl-amino]-propyl,        (methyl-piperidinyl)-propyl,        [(methanesulfonyl-ethyl)-piperazinyl]-ethyl,        [(cyano-ethyl)-piperazinyl]-ethyl,        [(methoxy-ethyl)-piperazinyl]-ethyl,        [(methoxy-ethyl)-methyl-amino]-propyl,        (cyanomethyl-methyl-amino)-propyl,        (cyanomethyl-methyl-amino)-ethyl,        [(methanesulfonyl-ethyl)-methyl-amino]-propyl,        (difluoro-piperidinyl)-propyl, (difluoro-piperidinyl)-ethyl,        [(cyano-ethyl)-methyl-amino]-propyl,        [(methanesulfonyl-ethyl)-methyl-amino]-ethyl,        [(trifluoro-ethyl)-piperazinyl]-ethyl,        [cyanomethyl-(methanesulfonyl-ethyl)-amino]-propyl,        [cyanomethyl-(methanesulfonyl-ethyl)-amino]-ethyl,        (cyanomethyl-piperazinyl)-propyl,        [(methanesulfonyl-ethyl)-piperazinyl]-propyl,        [(cyano-ethyl)-piperazinyl]-propyl,        [(trifluoro-ethyl)-piperazinyl]-propyl,        (methanesulfonyl-ethyl-amino)-ethyl,        [(cyano-ethyl)-piperidinyl]-methyl,        (cyanomethyl-piperidinyl)-methyl, (hydroxy-piperidinyl)-propyl,        [(methanesulfonyl-ethyl)-piperidinyl]-methyl,        piperidinyl-methyl, piperidinyl, imidazolyl-propyl,        1-methyl-[1,4]-diazepan-6-ol, methanesulfonyl-propyl,        (methanesulfonyl-ethyl-amino)-propyl, pyrrolidinyl-methyl,        methanesulfonyl-ethyl, (cyanomethyl-amino)-ethyl,        (cyanomethyl-amino)-propyl, (dioxo-thiomorpholinyl)-propyl,        (oxo-piperidinyl)-propyl, [(difluoro-ethyl)-methyl-amino]-ethyl,        morpholinyl-methyl, (hydroxy-pyrrolidinyl)-propyl,        (hydroxy-piperidinyl)-propyl, pyrrolidinyl-methyl,        (hydroxy-pyrrolidinyl)-propyl, methyl-piperidinyl,        (methyl-pyrrolidinyl)-methyl, morpholinyl-methyl,        pyrrolidinyl-methyl, (methyl-tetrahydro-pyridinyl)-methyl,        (cyano-ethyl)-piperidinyl, azetidinyl,        (methanesulfonyl-ethyl)-piperidinyl, (cyano-methyl)-piperidinyl,        isopropyl-piperidinyl, propyl-piperidinyl, acetyl-piperidinyl,        ethyl-piperidinyl, allyl-piperidinyl, tetrahydro-pyranyl,        (hydroxy-ethyl)-piperidinyl, (methyl-pyrrolidinyl)-methyl,        (methoxyethyl)-piperidinyl, piperidinyl,        (methoxy-ethyl)-azetidinyl,        (methoxy-methoxymethyl-ethyl)-piperidinyl,        (methoxy-acetyl)-piperidinyl, methoxycarbonyl-piperidnyl,        (hydroxy-acetyl)-piperidinyl, piperidine-carboxylic        acid-acetoxy-ethyl, piperidine-carboxylic        acid-acetoxy-methyl-ethyl, hydroxy-piperidinyl,        amino-cyclohexyl, piperidinyl, piperidine-carboxylic        acid-methyl-oxo-dioxolylmethyl, hydroxymethyl-piperidinyl,        (aminomethyl)-cyclohexyl, amino-methyl-cyclohexyl,        hydroxy-piperidinyl-methyl, morpholinyl, amino-cyclohexyl,        hydroxymethyl-piperidinyl, tetrahydro-pyranyl,        methanesulfonyl-propyl, amino-methyl-propyl, amino-cyclohexyl,        amino-methyl-cyclohexyl, (hydroxy-piperidinyl)-propyl,        piperidinyl, amino-propyl, morpholinyl-methyl, piperidinyl,        (tert-butoxycarbonyl-morpholinyl)-methyl, benzyl,        imidazolyl-ethyl, piperidinyl-ethyl, methoxyethyl,        (diethylamino)-(methoxyethyl), pyrrolidinyl-ethyl, acetamide and        methyl.

In another embodiment, the invention comprises a compound of formula(II)

wherein

-   -   X is a direct bond, —NR³— or —O—;    -   R² is aryl or substituted aryl, heteroaryl or substituted        heteroaryl,    -   R³, R⁴ and R⁵ are independently selected from hydrogen, alkyl        and substituted alkyl;    -   R⁶, R^(6a) and R^(6b) are independently selected from the group        consisting of one or more hydrogen, halogen, alkyl, alkoxy,        aryloxy, —CN, —NH₂, —OH, —COOH, —CH₂OR⁵, —CONHSO₂R⁵, —CONR⁴R⁵,        —NHalkyl, —NHCOalkyl, —NR⁴SO₂alkyl, —NR⁴SO₂NR⁴R⁵, —OCONR⁴R⁵,        —CF₃ and —OCF₃, two of which may be attached to the same ring        carbon atom provided that the resultant compound is chemically        stable;    -   R⁷ is hydrogen, alkyl or —NH₂, and    -   n is 0, 1, 2 or 3;        or a pharmaceutically acceptable salt or stereoisomer thereof.

In another embodiment, the invention comprises a compound of formulaIII,

wherein

-   -   X is a direct bond, —NR³— or —O—;    -   R² is aryl or substituted aryl, heteroaryl or substituted        heteroaryl,    -   R³, R⁴ and R⁵ are independently selected from hydrogen, alkyl        and substituted alkyl;    -   R⁶, R^(6a) and R^(6b) are independently selected from the group        consisting of one or more hydrogen, halogen, alkyl, alkoxy,        aryloxy, —CN, —NH₂, —OH, —COOH, —CH₂OR⁵, —CONHSO₂R⁵—CONR⁴R⁵,        —NHalkyl, —NHCOalkyl, —NR⁴SO₂alkyl, —NR⁴SO₂NR⁴R⁵, —OCONR⁴R⁵,        —CF₃ and —OCF₃, two of which may be attached to the same ring        carbon atom provided that the resultant compound is chemically        stable; and    -   n is 0, 1, 2 or 3;        or a pharmaceutically acceptable salt or stereoisomer thereof.

In another embodiment, the invention comprises a compound of formulaIII, wherein

-   -   R² is phenyl, substituted phenyl, pyridinyl, substituted        pyridinyl, pyrimidinyl, substituted pyrimidinyl, oxazole,        substituted oxazole, thiazole, substituted thiazole, pyrazinyl        or substituted pyrazinyl;    -   R⁶, R^(6a) and R^(6b) are independently selected from the group        consisting of one or more hydrogen, —NH₂, OH, alkoxy, —CONR⁴R⁵,        —NR⁴SO₂alkyl, —NR⁴SO₂NR⁴R⁵, —OCONR⁴R⁵, —NHalkyl and —NHCOalkyl;    -   X is —NH—; and    -   n is 1 or 2.

Preferred compounds of the invention include the following

-   5-[(4-Amino-1-piperidinyl)methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine,-   5-[(4-Amino-1-piperidinyl)methyl]-N-2-naphthalenylpyrrolo[2,1-f][1,2,4]triazin-4-amine,-   5-[(4-Amino-1-piperidinyl)methyl]-N-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine,-   5-[(4-Amino-1-piperidinyl)methyl]-N-(3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine,-   5-[(4-Amino-1-piperidinyl)methyl]-N-(3-ethynylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine,-   5-[(4-aminopiperidin-1-yl)methyl]-N-(4-fluoro-3-methoxyphenyl)pyrrolo[2,1-][1,2,4]triazin-4-amine,-   (3R,4R)-4-amino-1-[[4-[(3-chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol,-   (3S,4S)-4-amino-1-[[4-[(3-chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol,-   (3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol,-   (3S,4S)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol,-   (3R,4R)-4-amino-1-[[4-[(3-methoxy-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol,-   (3R,4R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-j]-[1,2,4]-triazin-5-yl}-methyl)piperidin-3-ol,-   (3R,4R)-4-amino-1-({4-[(3-ethoxyphenyl)-amino]-pyrrolo[2,1-f]-[1,2,4]triazin-5-yl}-methyl)piperidin-3-ol,-   (3R,4R)-4-amino-1-{[4-(2-naphthylamino)-pyrrolo[2,1-f][1,2,4]-triazin-5-yl]methyl}piperidin-3-ol,-   (3R,4R)-4-amino-1-({4-[(3-methoxy-4-methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol,-   (3R,4R)-4-amino-1-({4-[(3-bromophenyl)amino]pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-ol,-   (3R,4R)-4-amino-1-({4-[(3-fluoro-5-methoxy-phenyl)amino]pyrrolo[2,1-[1,2,4]triazin-5-yl}-methyl)piperidin-3-ol,-   (3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol,-   (3R,4S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol,-   (3S,4R)-4-amino-1-({4-[(3-chlorophenyl)amino]-pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-ol,-   (3S,4R)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol,-   (3S,4R)-4-amino-1-({4-[(3-ethynylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol,-   (3R,4S)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol,-   (3R,4S)-4-amino-1-({4-[(3-chlorophenyl)amino]pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-ol,-   (3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl    carbamate,-   (3R,4R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-yl    carbamate,-   (3R,4R)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-yl    carbamate,-   (3S,4R)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-yl    carbamate,-   (3S,4R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-yl    carbamate,-   (3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-3-methylpiperidin-3-ol,-   (3R/S,5R/S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol,-   (3S,5S)-4-amino-1-({4-[(4-fluoro-3-methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidine-3,5-diol,-   (3R,5R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol,-   5-{[(3R,4R)-4-amino-3-methoxypiperidin-1-yl]methyl}-N-(3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine,-   5-(((4aR,8aR)-rel-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)methyl)-N-(3-methoxyphenyl)pyrrolo    [1,2-f][1,2,4]triazin-4-amine,-   (3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-(methylsulfonyl)piperidine-3-carboxamide,-   (3R,4R)-4-amino-1-({4-[(3-ethynylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-methylpiperidine-3-carboxamide,-   (3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-methylpiperidine-3-carboxamide,-   (3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3-carboxamide,-   ((3R,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]-triazin-5-yl)methyl)-4-((R)-1-phenylethylamino)piperidin-3-yl)methanol,-   N-[(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]urea,-   N-[(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]methanesulfonamide,    and-   N-[(3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]methanesulfonamide,    or a pharmaceutically acceptable salt thereof.

The following are definitions of terms that may be used in the presentspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification individually or as part of another group, unless otherwiseindicated.

The term “alkyl” refers to straight or branched chain unsubstitutedhydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbonatoms. The expression “lower alkyl” refers to unsubstituted alkyl groupsof 1 to 4 carbon atoms.

The term “substituted alkyl” refers to an alkyl group substituted by,for example, one to four substituents, such as, halo, hydroxy, alkoxy,oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino,aralkylamino, disubstituted amines in which the 2 amino substituents areselected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino,aralkanoylamino, substituted alkanoylamino, substituted arylamino,substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, sulfonamido, e.g. SO₂NH₂, substituted sulfonamido,nitro, cyano, carboxy, carbamyl, e.g. CONH₂, substituted carbamyl e.g.CONHalkyl, CONHaryl, CONHaralkyl or cases where there are twosubstituents on the nitrogen selected from alkyl, aryl or aralkyl;alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, e.g.,indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,homopiperazinyl and the like, and substituted heterocyclyl. Where notedabove where the substituent is further substituted it will be withalkyl, alkoxy, aryl or aralkyl.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,naphthyl, biphenyl and diphenyl groups, each of which may besubstituted.

The term “aralkyl” refers to an aryl or a substituted aryl group bondeddirectly through an alkyl group, such as benzyl.

The term “aryloxy” refers to an aryl or a substituted aryl group bondeddirectly through an alkoxy group, such as methoxy or ethoxy.

The term “substituted aryl” refers to an aryl group substituted by, forexample, one to four substituents such as alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, aralkyl, halo, trifluoromethoxy, trifluoromethyl,hydroxy, alkoxy, alkanoyl, alkanoyloxy, aryloxy, aralkyloxy, amino,alkylamino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol,alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl,alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonicacid, alkysulfonyl, sulfonamido, aryloxy and the like. The substituentmay be further substituted by hydroxy, halo, alkyl, alkoxy, alkenyl,alkynyl, aryl or aralkyl.

The term “heteroaryl” refers to an optionally substituted, aromaticgroup for example, which is a 4 to 7 membered monocyclic, 7 to 11membered bicyclic, or 10 to 15 membered tricyclic ring system, which hasat least one heteroatom and at least one carbon atom-containing ring,for example, pyridine, tetrazole, indazole.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having one to four double bonds.

The term “substituted alkenyl” refers to an alkenyl group substitutedby, for example, one to two substituents, such as, halo, hydroxy,alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl,sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl,pyridyl, pyrimidyl and the like.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having one to four triple bonds.

The term “substituted alkynyl” refers to an alkynyl group substitutedby, for example, a substituent, such as, halo, hydroxy, alkoxy,alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino,thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano,carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclyl,e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl and the like.

The term “cycloalkyl” refers to an optionally substituted, saturatedcyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and3 to 7 carbons per ring which may be further fused with an unsaturatedC₃-C₇ carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl,cyclododecyl, and adamantyl. Exemplary substituents include one or morealkyl groups as described above, or one or more groups described aboveas alkyl substituents.

The terms “heterocycle”, “heterocyclic” and “heterocyclyl” refer to anoptionally substituted, fully saturated or unsaturated, aromatic ornonaromatic cyclic group, for example, which is a 4 to 7 memberedmonocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclicring system, which has at least one heteroatom in at least one carbonatom-containing ring. Each ring of the heterocyclic group containing aheteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms,oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatomsmay also optionally be oxidized and the nitrogen heteroatoms may alsooptionally be quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, homopiperazinyl,2-oxohomopiperazinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, and triazolyl, and the like.

Exemplary bicyclic heterocyclic groups include2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl,benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,1-b]pyridinyl]or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, indazolyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like.

Exemplary substituents include one or more alkyl or aralkyl groups asdescribed above or one or more groups described above as alkylsubstituents.

Also included are smaller heterocyclyls, such as, epoxides andaziridines.

The term “carbocyclic ring” refers to stable, saturated or partiallyunsaturated monocyclic hydrocarbon rings of 3 to 7 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Theterm “optionally substituted” as it refers to “carbocyclic ring” hereinindicates that the carbocyclic ring may be substituted at one or moresubstitutable ring positions by one or more groups independentlyselected from alkyl (preferably lower alkyl), alkoxy (preferably loweralkoxy), nitro, monoalkylamino (preferably a lower alkylamino),dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl(preferably trifluoromethyl), alkanoyl, aminocarbonyl,monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferablylower alkyl amido), alkoxyalkyl (preferably a lower alkoxy[lower]alkyl),alkoxycarbonyl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy(preferably a lower alkylcarbonyloxy) and aryl (preferably phenyl), saidaryl being optionally substituted by halo, lower alkyl and lower alkoxygroups.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The compounds of formula I may form salts which are also within thescope of this invention. Pharmaceutically acceptable (i.e. non-toxic,physiologically acceptable) salts are preferred, although other saltsare also useful, e.g., in isolating or purifying the compounds of thisinvention.

The compounds of formula I may form salts with alkali metals such assodium, potassium and lithium, with alkaline earth metals such ascalcium and magnesium, with organic bases such as dicyclohexylamine,tributylamine, pyridine and amino acids such as arginine, lysine and thelike. Such salts can be formed as known to those skilled in the art.

The compounds for formula I may form salts with a variety of organic andinorganic acids. Such salts include those formed with hydrogen chloride,hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid,trifluoroacetic acid, oxalic acid, maleic acid, benzenesulfonic acid,toluenesulfonic acid and various others (e.g., nitrates, phosphates,borates, tartrates, citrates, succinates, benzoates, ascorbates,salicylates and the like). Such salts can be formed as known to thoseskilled in the art.

In addition, zwitterions (“inner salts”) may be formed.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of compounds according to the invention embraces all thepossible stereoisomers and their mixtures. It very particularly embracesthe racemic forms and the isolated optical isomers having the specifiedactivity. The racemic forms can be resolved by physical methods, suchas, for example, fractional crystallization, separation orcrystallization of diastereomeric derivatives or separation by chiralcolumn chromatography. The individual optical isomers can be obtainedfrom the racemates from the conventional methods, such as, for example,salt formation with an optically active acid followed bycrystallization.

Compounds of the formula I may also have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., thecompound for formulas J) is a prodrug within the scope and spirit of theinvention.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

-   -   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)        and Methods in Enzymology, Vol. 112, p. 309-396, edited by K.        Widder, et al. (Academic Press, 1985);    -   b) A Textbook of Drug Design and Development, edited by        Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and        Application of Prodrugs,” by H. Bundgaard, p. 113-191 (1991);        and    -   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992).

It should further be understood that solvates (e.g., hydrates) of thecompounds of formula I are also with the scope of the present invention.Methods of solvation are generally known in the art.

Utility

The present invention is based on the discovery that certainpyrrolotriazines are inhibitors of protein kinases. More specifically,pyrrolotriazines such as those described in this invention inhibit theprotein tyrosine kinase activity of members of the HER family ofreceptors. These inhibitors will be useful in the treatment ofproliferative diseases that are dependent on signaling by one or more ofthese receptors. Such diseases include psoriasis, rheumatoid arthritis,and solid tumors of the lung, head and neck, breast, colon, ovary, andprostate. The invention relates to a pharmaceutical composition ofcompound of formula I, or pharmaceutically acceptable salt or hydratethereof, and a pharmaceutically acceptable carrier in the treatment ofhyperproliferative disorder in mammal. In particular, the saidpharmaceutical composition is expected to inhibit the growth of thoseprimary and recurrent solid tumors which are associated with HER1 (EGFreceptor) and HER2, especially those tumors which are significantlydependent on HER1 or HER2 for their growth and spread, including forexample, cancers of the bladder, squamous cell, head, colorectal,oesophageal, gynecological (such as ovarian), pancreas, breast,prostate, vulva, skin, brain, genitourinary tract, lymphatic system(such as thyroid), stomach, larynx and lung. In another embodiment, thecompounds of the present invention are also useful in the treatment ofnoncancerous disorders such as psoriasis and rheumatoid arthritis.

Thus according to a further aspect of the invention there is providedthe use of a compound of the formula I, or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for use in theproduction of an antiproliferative effect in a warm-blooded animal suchas a human being.

According to a further feature of the invention there is provided amethod for producing an antiproliferative effect in a warm-bloodedanimal, such as a human being, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof as definedherein before.

By virtue of their ability to inhibit HER1, HER2, and HER4 kinases,compounds of the present invention can be used for the treatment ofproliferative diseases, including psoriasis and cancer. The HER1receptor kinase has been shown to be expressed and activated in manysolid tumors including head and neck, prostate, non-small cell lung,colorectal, and breast cancer. Similarly, the HER2 receptor kinase hasbeen shown to be overexpressed in breast, ovarian, lung and gastriccancer. Monoclonal antibodies that downregulate the abundance of theHER2 receptor or inhibit signaling by the HER1 receptor have shownanti-tumor efficacy in preclincal and clinical studies. It is thereforeexpected that inhibitors of the HER1 and HER2 kinases will have efficacyin the treatment of tumors that depend on signaling from either of thetwo receptors. In addition, these compounds will have efficacy ininhibiting tumors that rely on HER receptor heterodimer signaling. Thesecompounds are expected to have efficacy either as single agent or incombination (simultaneous or sequentially) with other chemotherapeuticagents such as Taxol®, adriamycin, and cisplatin. Since HER1 and HER2signaling has been shown to regulate expression of angiogenic factorssuch as vascular endothelial growth factor (VEGF) and interleukin 8(IL8), these compounds are expected to have anti-tumor efficacyresulting from the inhibition of angiogenesis in addition to theinhibition of tumor cell proliferation and survival. The HER2 receptorhas been shown to be involved in the hyperproliferation of synovialcells in rheumatoid arthritis, and may contribute to the angiogeniccomponent of that inflammatory disease state. The inhibitors describedin this invention are therefore expected to have efficacy in thetreatment of rheumatoid arthritis. The ability of these compounds toinhibit HER1 further adds to their use as anti-angiogenic agents. Seethe following documents and references cited therein: Schlessinger J.,“Cell signaling by receptor tyrosine kinases”, Cell 103(2), p. 211-225(2000); Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J.,Scholl, S., Fehrenbacher, L., Wolter, J. M., Paton, V., Shak, S.,Lieberman, G., and Slamon, D. J., “Multinational study of the efficacyand safety of humanized anti-HER2 monoclonal antibody in women who haveHER2-overexpressing metastatic breast cancer that has progressed afterchemotherapy for metastatic disease”, J. of Clin. Oncol. 17(9), p.2639-2648 (1999); Baselga, J., Pfister, D., Cooper, M. R., Cohen, R.,Burtness, B., Bos, M., D'Andrea, G., Seidman, A., Norton, L., Gunnett,K., Falcey, J., Anderson, V., Waksal, H., and Mendelsohn, J., “Phase Istudies of anti-epidermal growth factor receptor chimeric antibody C225alone and in combination with cisplatin”, J. Clin. Oncol. 18(4), p.904-914 (2000); Satoh, K., Kikuchi, S., Sekimata, M., Kabuyama, Y.,Homma, M. K., and Homma Y., “Involvement of ErbB-2 in rheumatoidsynovial cell growth”, Arthritis Rheum. 44(2), p. 260-265 (2001).

The antiproliferative treatment defined herein before may be applied asa sole therapy or may involve, in addition to a compound of theinvention, one or more other substances and/or treatments. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate administration of the individual components of the treatment.The compounds of this invention may also be useful in combination withknown anti-cancer and cytotoxic agents and treatments, includingradiation. If formulated as a fixed dose, such combination productsemploy the compounds of this invention within the dosage range describedbelow and the other pharmaceutically active agent within its approveddosage range. Compounds of formula I may be used sequentially with knownanticancer or cytotoxic agents and treatment, including radiation when acombination formulation is inappropriate.

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment in addition to the antiproliferative treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapymay cover three main categories of therapeutic agent:

-   -   (i) antiangiogenic agents that work by different mechanisms from        those defined hereinbefore (for example, linomide, inhibitors of        integrin αvβ3 function, angiostatin, razoxane);    -   (ii) cytostatic agents such as antiestrogens (for example,        tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene),        progestogens (for example, megestrol acetate), aromatase        inhibitors (for example, anastrozole, letrozole, borazole,        exemestane), antihormones, antiprogestogens, antiandrogens (for        example, flutamide, nilutamide, bicalutamide, cyproterone        acetate), LHRH agonists and antagonists (for example, gosereline        acetate, leuprolide), inhibitors of testosterone        5α-dihydroreductase (for example, finasteride),        farnesyltransferase inhibitors, anti-invasion agents (for        example, metalloproteinase inhibitors such as marimastat and        inhibitors of urokinase plasminogen activator receptor function)        and inhibitors of growth factor function, (such growth factors        include for example, EGF, FGF, platelet derived growth factor        and hepatocyte growth factor, such inhibitors include growth        factor antibodies, growth factor receptor antibodies such as        Avastin® (bevacizumab) and Erbitux® (cetuximab); tyrosine kinase        inhibitors and serine/threonine kinase inhibitors); and    -   (iii) antiproliferative/antineoplastic drugs and combinations        thereof, as used in medical oncology, such as antimetabolites        (for example, antifolates such as methotrexate,        fluoropyrimidines such as 5-fluorouracil, purine and adenosine        analogues, cytosine arabinoside); Intercalating antitumour        antibiotics (for example, anthracyclines such as doxorubicin,        daunomycin, epirubicin and idarubicin, mitomycin-C,        dactinomycin, mithramycin); platinum derivatives (for example,        cisplatin, carboplatin); alkylating agents (for example,        nitrogen mustard, melphalan, chlorambucil, busulphan,        cyclophosphamide, ifosfamide nitrosoureas, thiotepa; antimitotic        agents (for example, vinca alkaloids like vincristine,        vinorelbine, vinblastine and vinflunine, and taxoids such as        Taxol® (paclitaxel), Taxotere® (docetaxel) and newer        microbtubule agents such as epothilone analogs, discodermolide        analogs, and eleutherobin analogs); topoisomerase inhibitors        (for example, epipodophyllotoxins such as etoposide and        teniposide, amsacrine, topotecan, irinotecan); cell cycle        inhibitors (for example, flavopyridols); biological response        modifiers and proteasome inhibitors such as Velcade®        (bortezomib).

As stated above, the formula I compounds of the present invention are ofinterest for their antiproliferative effects. Such compounds of theinvention are expected to be useful in a wide range of disease statesincluding cancer, psoriasis, and rheumatoid arthritis.

More specifically, the compounds of formula I are useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing:

-   -   carcinoma, including that of the bladder, breast, colon, kidney,        liver, lung, including small cell lung cancer, esophagus, gall        bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,        and skin, including squamous cell carcinoma;    -   tumors of mesenchymal origin, including fibrosarcoma and        rhabdomyosarcoma;    -   tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and    -   other tumors, including melanoma, seminoma, teratocarcinoma, and        osteosarcoma.

Due to the key role of kinases in the regulation of cellularproliferation in general, inhibitors could act as reversible cytostaticagents which may be useful in the treatment of any disease process whichfeatures abnormal cellular proliferation, e.g., benign prostatehyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formationand inflammatory bowel disease

The compounds of formula I are especially useful in treatment of tumorshaving a high incidence of tyrosine kinase activity, such as colon,lung, and pancreatic tumors. By the administration of a composition (ora combination) of the compounds of this invention, development of tumorsin a mammalian host is reduced.

Compounds of formula I may also be useful in the treatment of diseasesother than cancer that may be associated with signal transductionpathways operating through growth factor receptors such as HER1 (EGFreceptor), HER2, or HER4.

The pharmaceutical compositions of the present invention containing theactive ingredient may be in a form suitable for oral use, for example,as tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example,microcrystalline cellulose, sodium crosscarmellose, corn starch, oralginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to mask the unpleasant taste ofthe drug or delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a water soluble taste masking material such ashydroxypropyl-methylcellulose or hydroxypropyl-cellulose, or a timedelay material such as ethyl cellulose, cellulose acetate buryrate maybe employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, sex and response of the individual patient, as well as theseverity of the patient's symptoms.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent or treatment within its approveddosage range. Compounds of formula I may also be administeredsequentially with known anticancer or cytotoxic agents when acombination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of formula I may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent(s).

The compounds may be administered in a dosage range of about 0.05 to 200mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2to 4 divided doses.

Biological Assays

HER1, HER2 or HER4 Kinase Assays

Compounds of interest were assayed in a kinase buffer that contained 20mM Tris.HCl, pH 7.5, 10 mM MnCl₂, 0.5 mM dithiothreitol, bovine serumalbumin at 0.1 mg/ml, poly(glu/tyr, 4:1) at 0.1 mg/ml, 1 □M ATP, and 4□Ci/ml [□-³³P]ATP. Poly(glu/tyr, 4:1) is a synthetic polymer that servesas a phosphoryl acceptor and is purchased from Sigma Chemicals. Thekinase reaction is initiated by the addition of enzyme and the reactionmixtures were incubated at 26° C. for 1 h. The reaction is terminated bythe addition of EDTA to 50 mM and proteins are precipitated by theaddition of trichloroacetic acid to 5%. The precipitated proteins arerecovered by filtration onto Packard Unifilter plates and the amount ofradioactivity incorporated is measured in a Topcount scintillationcounter.

For the preparation of recombinant HER1 and HER4, the cytoplasmicsequences of the receptors were expressed in insect cells as GST fusionproteins, which were purified by affinity chromatography. Thecytoplasmic sequence of HER2 was subcloned into the baculovirusexpression vector pBlueBac4 (Invitrogen) and was expressed as anuntagged protein in insect cells. The recombinant protein was partiallypurified by ion-exchange chromatography.

The instant compounds inhibit HER1, HER2, and HER4 kinases with IC50values between 0.001 to 25 μM. Preferred compounds have IC₅₀ valuesbetween 0.001-5.0 μM. More preferred compounds have IC₅₀ values between0.001-1.0 μM. Most preferred compounds have IC₅₀ values between0.001-0.1 μM.

Methods of Preparation

Certain compounds of formula I may generally be prepared according tothe following schemes and the knowledge of one skilled in the art.Supplemental preparation information may also be found in co-pendingU.S. patent application Ser. No. 09/573,829 filed May 18, 2000 andInternational Publication Number WO 00/71129, both herein incorporatedby reference.

Step 1

The first step of Scheme 1 is accomplished by treating Compound i (Ref.WO 03/042172 A2) with a thiol such as methanethiol or butanethiol ortheir sodium salts in an anhydrous solvent such as THF under an inertatmosphere such as N₂ to give Compound ii.

Step 2

Halogenation of the 5-methyl group of Compound ii is affected bytreatment with a halogenating reagent such as N-bromosuccinimide. Thereaction is preformed under an inert atmosphere such Ar in the presenceof a catalyst such as dibenzoyl peroxide or 2,2′-azobisisobutyronitrileand gives the 5-halomethyl-pyrrolotrazine Compound iii.

Step 3

Treatment of Compound iii with a primary or secondary amine or alcoholin the presence of a base such as NaHCO₃ or triethylamine ordiisopropylethylamine in a solvent such as acetonitrile orN,N-dimehylformamide affords intermediate Compound iv.

Step 4

Treatment of intermediate Compound iv with an aniline in the presence ofHgCl₂ in a solvent such as toluene affords the 4-substitutedpyrrolotriazines Compound v.

Step 5

Alternatively compounds of formula iv may be treated with an appropriateoxidizing agent such as m-chloroperbenzoic acid in a solvent such asCH₂Cl₂ to afford sulfones vi.

Step 6

Sulfones vi may be converted to compound v by treatment with a primaryor secondary amine or alcohol in an inert solvent such as CH₂Cl₂

Alternatively, compounds of general formula I may be prepared as shownin Scheme 2.

Step 1

The first step of Scheme 2 is accomplished by treating Compound i (Ref.WO 03/042172 A2) with a halogenating reagent such as N-bromosuccinimideunder an inert atmosphere such as Ar. The reaction is performed in anappropriate solvent such as CCl₄ in the presence of a catalyst such asdibenzoyl peroxide or 2,2′-azobisisobutyronitrile to afford thedihalopyrrolotrazine Compound vii.

Step 2

Compound vii may be converted to ammonium salt Compound viii bytreatment with a tertiary base such as triethylamine in an anhydroussolvent such as THF.

Step 3

Treatment of Compound viii with an amine or its anion in an anhydroussolvent such as acetonitrile, chloroform or THF affords ammonium saltCompound ix.

Step 4

Conversion of Compound ix to pyrrolotriazine Compound v may beaccomplished by treatment of Compound ix with a primary or secondaryamine or alcohol in the presence of a base such as diisopropylethylaminein a solvent such as acetonitrile.

Compounds prepared by the above methods having general formula x inScheme 3 in which the 5-methylsubstituent contains a protecting groupsuch as t-butoxycarbonyl may further be modified by removal of theprotecting group in Step 1 by treatment with anhydrous HCl in diethylether or 1,4-dioxane or by treatment of a solution of the compound inCH₂Cl₂ with trifluoroacetic acid to prepare the free amines xi. Furthermodification may be accomplished in Step 2 by treating Compound xi witha carbonyl compound such as propanal in the presence of a reducing agentsuch as sodium triacetoxyborohydride in a solvent such as CH₂Cl₂ toafford substituted amines xii.

Further compounds may be prepared as shown in Scheme 4. In Step 1,compound ix may be treated with a secondary amine such asbis-(2-chloroethyl)amine in an appropriate solvent such as acetonitrilein the presence of a base such as diisopropylethylamine to affordCompound xii. Compound xii may further be treated with a nucleophilesuch as hydrazine in Step 2 to afford Compund xiii.

Further 5-substituted pyrrolotriazines may be prepared according to

Step 1

Compound i may be treated with two equivalents of a brominating reagentsuch as N-bromosuccinimide in a solvent such as CCl₄ at elevatedtemperature. The resulting 5-dibromopyrrolotriazine may be converted tothe corresponding dimethylacetal using methanol in the presence of abase such as NaHCO₃ and then to the aldehyde Compound xiv by treatingthe intermediate acetal with an acid such as trifluoroacetic acid in thepresence of water.

Step 2

Treatment of aldehyde Compound xiv with an organometallic reagent suchas a Grignard reagent in an anhydrous solvent such as THF affordsalcohol xv.

Step 3

Alcohol xv may be treated with a primary or secondary amine or alcoholin the presence of a base such as NaHCO₃ in an appropriate solvent suchas acetonitrile to afford compounds of formula xvi.

In addition, other compounds of formula I may be prepared usingprocedures generally known to those skilled in the art. In particular,the following examples provide additional methods for the preparation ofthe compounds of this invention.

The invention will now be further described by the following workingexamples(s), which are preferred embodiments of the invention. Alltemperatures are in degrees Celsius (° C.) unless otherwise indicated.“HPLC Ret Time” is the HPLC retention time that was obtained under thefollowing conditions: column type and length, gradient time [unlessotherwise indicated, all gradients started with 100% solvent A (10%MeOH, 90% H₂O, 0.1% TFA) and ended with 100% solvent B (90% MeOH, 10%H₂O, 0.1% TFA)], flow rate (mL/min). UV detection was always conductedat 220 nM. These examples are illustrative rather than limiting and itis to be understood that there may be other embodiments that fall withinthe spirit and scope of the invention as defined by the claims appendedhereto.

EXAMPLE 15-[(4-Amino-1-piperidinyl)methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

1A. Preparation of5-methyl-4-methylsulfanyl-pyrrolo[2,1f][1,2,4]triazine

To a solution of 4-chloro-5-methyl-pyrrolo[2,1f][1,2,4]triazine (4.02 g,24.0 mmol)(Ref. WO 03/042172 A2) in dry THF (200 ml) sparged with N₂ at0° C. was added NaSMe (1.85 g, 26.3 mmol). The sparging was continuedfor 5 min. The reaction mixture was then stirred at rt overnight,concentrated in vacuo to about 50 ml volumn left. Diluted with H₂O (280ml) and stirred at 0° C. The solid was filtered, washed with cold water,dried to give 1A (3.91 g, 91%). It had an analytical HPLC retentiontime=3.38 min. (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at220 nm) and a LC/MS M⁺+1=180.

1B. Preparation of [1-(4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl)-piperidin-4-yl]-carbamic acidtert-butyl ester

A mixture of 1A (1.94 g, 10.8 mmol), benzoyl peroxide (0.262 g, 1.08mmol), NBS (2.12 g, 11.90 mmol) in CCl₄ (100 ml) was sparged with N₂,then immediately heated to 85° C. for 1.5 h. The mixture was cooled tort and the precipitate was filtered off. The filtrate was concentratedin vacuo, diluted with dichloroethane (35 ml), and DIEA (2.24 ml, 12.96mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (2.38 g, 11.90mmol) were added. The reaction mixture was stirred at rt for 1 h. Themixture was diluted with saturated NaHCO₃ (70 ml) and extracted withEtOAc (3×100 ml). The combined EtOAc extracts were washed with brine(1×100 ml), dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica gel flash column to give 1B (2.87 g,70%)(0.1%-2% MeOH—CH₂Cl₂). It had an analytical HPLC retention time=2.12min. (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm)and a LC/MS M⁺+1=378.

1C. Preparation of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine

A mixture of 4-chloro-5-methyl-pyrrolo[2,1f][1,2,4]triazine (2.0 g,11.93 mmol) (Ref WO 03/042172 A2) and AIBN (195 mg, 1.19 mmol) in CCl₄(80 ml) under N₂ was heated to 100° C. for 5 min, NBS (2.55 g, 14.3mmol) was added. The reaction mixture was stirred for 10 min, thencooled to rt, filtered. The CCl₄ layer was washed with dilute NaHCO₃aqueous solution, dried (MgSO₄), filtered and concentrated to give1C(2.70 g, 92%).

1D. Preparation of (4-chloro-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl)-triethyl-ammonium bromide

A mixture of 1C (2.7 g, 11 mmol), Et₃N (5 ml, 36 mmol) in THF (20 ml)was stirred at rt for 12 h. The solid was filtered and rinsed with THFand Et₂O, dried to give 1D (3.38 g, 89%). It had an analytical HPLCretention time=0.776 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺=267.

1E. Preparation of [4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-triethyl-ammonium bromidehydrochloride

A mixture of 1C (1.0 g, 2.2 mmol) and 3-chloro-4-fluoro-phenylamine (418mg, 2.87 mmol) in CHCl₃ (10 ml) was heated at 50° C. for 2 h. The solidwas filtered and rinsed with CHCl₃, dried to give 1E (1.24 g, 87.4%). Ithad an analytical HPLC retention time=2.19 min. (Chromolith SpeedROD4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺=376.

1F. Preparation of{1-[4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

Method One:

A mixture of 1B (30 mg, 0.08 mmol), 3-chloro-4-fluoro-phenylamine (11mg, 0.08 mmol) and HgCl₂ (24 mg, 0.088 mmol) in toluene (2 ml) washeated to reflux for 8 h. Cooled to rt, diluted with EtOAc (5 ml) andfiltered. The filtrate was concentrated, and the residue was purified byprep HPLC to give 1F as an oil.

Method Two:

To a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (4.1 g,20.3 mmol) in CH₃CN (55 ml) at 70° C. was added a mixture of 1E (9.1 g,18.4 mmol) and DIPEA (3.2 ml, 18.4 mmol) in CH₃CN (40 ml) dropwise in aperiod of 40 min. The reaction mixture was stirred at 70° C. for 1 h,then cooled to rt, after which H₂O (155 ml) was added slowly. The solidwas filtered and rinsed with 15% CH₃CN/H₂O, then H₂O, and ried undervacuum to give 1F (7.84 g, 90%). It had an analytical HPLC retentiontime=2.73 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) anda LC/MS M⁺+1=475.

1G. Preparation of5-[(4-amino-1-piperidinyl)methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Compound 1F (from Method one) was treated 20% TFA/CH₂Cl₂ (3 ml) at 0°C., then stirred at rt for 2 h. The reaction mixture was concentratedand purified by prep HPLC to give the product as the TFA salt, which wastreated with saturated NaHCO₃ to give the ree base 1G (4 mg, 13% for twosteps). It had an analytical HPLC retention time=1.49 min. (ChromolithSpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=375.

EXAMPLE 25-[(4-Amino-1-piperidinyl)methyl]-N-4-pyridinylpyrrolo[2,1-f][1,2,4]triazin-4-amine

To a mixture of pyridin-4-ylamine (34 mg, 0.361 mmol) in THF (500 μl)was added 1N NaHMDS in THF (722 μl, 0.722 mmol). The mixture was cooledto 0° C. and a suspension of 1D (125 mg, 0.27 mmol) in DMF (800 μl) wasadded. The mixture was stirred at this temperature for 0.5 h. andpiperidin-4-yl-carbamic acid tert-butyl ester (144 mg, 0.72 mmol) wasadded to the cold mixture. The reaction mixture was heated to 50° C. for10 min and concentrated to remove THF. TFA (1 ml) was added, the mixturewas stirred until the protecting group was removed (2 h) (progress wasmonitored by HPLC). TFA was removed in vacuo and saturated NaHCO₃ wasadded. The mixture was extracted with EtOAc and the combined extractswere dried, concentrated and triturated first with Et2O to give thetitle compound (46 mg, 53%). Analytical HPLC retention time=0.51 min(Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺+1=324.

EXAMPLES 3 TO 37

Compounds 3 to 37 were prepared using a similar process as the d inExample 2 utilizing the corresponding amines. HPLC Ex. [M + Ret Time # RCompound Name H] (min) 3

5-[(4-Amino-1-piperidinyl)methyl]-N-4-pyrimidinylpyrrolo[2,1-f][1,2,4]triazin-4- amine 325 0.65 (b) 4

5-[(4-Amino-1-piperidinyl)methyl]-N-pyrazinylpyrrolo[2,1-f][1,2,4]triazin-4- amine 325 1.02 (b) 5

5-[(4-Amino-1-piperidinyl)methyl]-N-(4- methyl-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 338 0.71 (b) 6

5-[(4-Amino-1-piperidinyl)methyl]-N-(5- methyl-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 338 0.80 (b) 7

5-[(4-Amino-1-piperidinyl)methyl]-N-(2-chloro-4-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 371 1.61 (b)8

5-[(4-Amino-1-piperidinyl)methyl]-N-2-naphthalenylpyrrolo[2,1-f][1,2,4]triazin-4- amine 373 1.81 (b) 9

5-[(4-Amino-1-piperidinyl)methyl]-N-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine 323 1.06 (b) 10

5-[(4-Amino-1-piperidinyl)methyl]-N-(6- methyl-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 338 0.60 (b) 11

5-[(4-Amino-1-piperidinyl)methyl]-N-2-pyrimidinylpyrrolo[2,1-f][1,2,4]triazin-4- amine, trifluoroacetic acidsalt (1:1) 325 1.00 (b) 12

5-[(4-Amino-1-piperidinyl)methyl]-N-(4-methyl-2-pyrimidinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine,trifluoroacetic acid salt (1:1) 339 1.03 (b) 13

5-[(4-Amino-1-piperidinyl)methyl]-N-(4,6-dimethyl-2-pyrimidinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine,trifluoroacetic acid salt (1:1) 353 1.08 (b) 14

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3-quinolinamine, trifluoroacetic acid salt (1:1)374 1.03 (b) 15

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-5-quinolinamine, trifluoroacetic acid salt (1:1)374 0.64 (b) 16

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-quinolinamine, trifluoroacetic acid salt (1:1)374 0.80 (b) 17

5-[(4-Amino-1-piperidinyl)methyl]-N-(6- chloro-3-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 358 1.03 (b)18

5-[(4-Amino-1-piperidinyl)methyl]-N-(6- methoxy-3-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 354 0.98 (b)19

5-[(4-Amino-1-piperidinyl)methyl]-N-(5- bromo-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 402 1.63 (b)20

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-8-quinolinamine, trifluoroacetic acid salt (1:1)374 0.92 (b) 21

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-5-isoquinolinamine, trifluoroacetic acid salt(1:1) 374 0.59 (b) 22

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-quinolinamine, trifluoroacetic acid salt (1:1)374 1.49 (b) 23

5-[(4-Amino-1-piperidinyl)methyl]-N-(5- chloro-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 374 1.55 (b)24

5-[(4-Amino-1-piperidinyl)methyl]-N-(4- methoxy-6-methyl-2-pyrimidinyl)pyrrolo[2,1-f][1,2,4]triazin-4- amine, trifluoroacetic acidsalt (1:1) 369 1.03 (b) 25

5-[(4-Amino-1-piperidinyl)methyl]-N-(6- ethyl-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 352 1.91 (b)26

5-[(4-Amino-1-piperidinyl)methyl]-N-(6-methoxy-4-pyrimidinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine,trifluoroacetic acid salt (1:1) 355 1.25 (b) 27

N-[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-6-isoquinolinamine, trifluoroacetic acid salt(1:1) 374 1.85 (b) 28

5-[(4-Amino-1-piperidinyl)methyl]-N-(3- methyl-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 338 1.67 (b)29

5-[(4-Amino-1-piperidinyl)methyl]-N-(4- ethyl-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 352 1.00 (b)30

5-[(4-Amino-1-piperidinyl)methyl]-N-(6- bromo-2-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 402 1.62 (b)31

5-[(4-Amino-1-piperidinyl)methyl]-N-(2,6-dimethyl-4-pyrimidinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine,trifluoroacetic acid salt (1:1) 353 0.89 (b) 32

5-[(4-Amino-1-piperidinyl)methyl]-N-[6- (methoxymethyl)-4-pyrimidinyl]-pyrrolo[2,1-f][1,2,4]triazin-4-amine 369 1.12 (b) 33

5[(4-Amino-1-piperidinyl)methyl]N-(6- methyl-3-pyridazinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 339 0.88 (b)34

5-[(4-Amino-1-piperidinyl)methyl]-N-(5-methyl-3-pyridazinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine,trifluoroacetic acid salt (1:1) 339 0.97 (b) 35

5-[(4-Amino-1-piperidinyl)methyl]-N-(6-chloro-3-pyridazinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine,trifluoroacetic acid salt (1:1) 359 1.29 (b) 36

5-[(4-Amino-1-piperidinyl)methyl]-N-(2- chloro-4-pyridinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 358 1.11 (b)37

5-[(4-Amino-1-piperidinyl)methyl]-N-(6- fluoro-5-methyl-3-pyridinyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, trifluoroacetic acidsalt (1:1)  35 1.05 (b)

EXAMPLES 38 TO 121

Method One:

Compounds (with HPLC note (a)) were prepared by the following standardmethod.

In a 1 dram vial was added ID (55.0 mg, 0.16 mmol), aniline (0.16 mmol,1.0 eq) and CH₃CN (1 ml). The mixture was shaken at 65° C. overnight. Tothis mixture was added piperidin-4-yl-carbamic acid tert-butyl ester(34.9 mg, 0.17 mmol) followed by addition of DIEA (28 μl, 0.16 mmol).The reaction was continued at 65° C. for 3 h. The mixture wasconcentrated; the residue was purified by Prep HPLC, and the desiredfraction was collected and concentrated. The obtained residue was driedunder high vacuum overnight.

To the above residue was added CH₂Cl₂ (1.5 ml) and TFA (0.2 ml), and thereaction mixture was shaken at rt for 2 h. The mixture was concentrated,and dried in speed vacuum overnight to give the solid product. FurtherPrep HPLC was used only when the solid was impure.

Method Two:

Compounds (with HPLC note (b)) were prepared by the following standardmethod.

A mixture of 1D (75 mg, 0.216 mmol) and anilines (1.0 eq, 0.216 mmol) inN,N-dimethyl acetamide (0.5 ml) in a small vial was heated at 70° C. for3-5 hrs until a clear solution obtained. HPLC was used to follow theprogress of the reaction. The reaction mixture was cooled to rt andpiperidin-4-yl-carbamic acid tert-butyl ester (43 mg, 0.216 mmol) wasadded, followed by N,N-diisopropylethylamine (75 μl). The reactionmixture again was heated to 70° C. overnight. Upon cooling, the reactionmixture was diluted with CH₂Cl₂ (0.5 ml) and cooled to 0° C. TFA (1.0ml) was added and the mixture was stirred at ambient temperatureovernight. The solvent was removed under reduced pressure (speedVac) andthe residue was taken into methanol and purified by Prep HPLC to givethe desired product. HPLC [M + Ret Time Ex. R Compound Name H] (min) 38

3-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-N-methyl benzamide 380.25 0.91 (a) 39

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-(4-chlorophenoxy)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 449.20 2.59(a) 40

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-(phenylmethoxy)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 429.26 2.183(a) 41

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-ethylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 351.28 1.64 (a) 42

3-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1- f][1,2,4]triazin-4-yl]amino]benzamide 366.25 0.76 (a) 43

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-(1-methylethoxy)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 381.27 1.66(a) 44

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-ethoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 367.26 1.44 (a) 45

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-(trifluoromethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 391.181.71 (a) 46

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-(1-methylethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 365.29 1.89 (a)47

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-(1-(trifluoromethoxy)phenyl]pyrrolo [2,1-f][1,2,4]triazin-4-amine 407.191.90 (a) 48

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,5-dimethoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 383.24 1.32 (a) 49

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,5-dichlorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 391.13 1.85 (a) 50

4-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-2- chlorobenzonitrile 382.19 1.63 (a) 51

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,5-dimethylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 351.28 1.56 (a) 52

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,5-difluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 359.24 1.14 (a) 53

5-[(4-Amino-1-piperidinyl)methyl]- N-(2-chloro-5-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 371.21 1.38 (a) 54

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-fluoro-3-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 355.27 1.33 (a) 55

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,4-dimethylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 351.28 1.58 (a) 56

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-methyl-3-(trifluoromethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 405.212.10 (a) 57

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-chloro-3-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 371.21 1.74 (a) 58

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,4-difluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 359.23 1.16 (a) 59

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-bromo-2-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 419.08 1.55 (a) 60

5-[(4-Amino-1-piperidinyl)methyl]- N-(2-fluoro-4-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 355.22 1.42 (a) 61

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-bromo-2-chlorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 435.08 1.68 (a) 62

5-[(4-Amino-1-piperidinyl)methyl]- N-(2,4-dimethylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 351.24 1.36 (a) 63

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-bromo-3-(trifluoromethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 469.122.35 (a) 64

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 425.132.26 (a) 65

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-fluoro-4-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 355.22 1.51 (a) 66

5-[(4-Amino-1-piperidinyl)methyl]- N-[3-bromo-4-(trifluoromethoxy)phenyl]pyrrolo [2,1-f][1,2,4]triazin-4-amine 485.112.43 (a) 67

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-fluoro-3-(trifluoromethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 409.171.88 (a) 68

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-fluoro-4-methoxyphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 371.23 0.76 (a) 69

5-[(4-Amino-1-piperidinyl)methyl]- N-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrrolo[2,1 -f][1,2,4]triazin-4- amine 381.23 1.24 (a) 70

5-[(4-Amino-1-piperidinyl)methyl]- N-(2,5-difluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 359.20 1.13 (a) 71

5-[(4-Amino-1-piperidinyl)methyl]- N-(2-fluoro-5-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 355.22 1.35 (a) 72

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-chloro-2-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 375.19 1.45 (a) 73

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-methoxy-4-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 367.25 1.48 (a) 74

5-[(4-Amino-1-piperidinyl)methyl]- N-(5-chloro-2-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 375.18 1.44 (a) 75

5-[(4-Amino-1-piperidinyl)methyl]- N-(2,3-difluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 359.21 1.16 (a) 76

5-[(4-Amino-1-piperidinyl)methyl]- N-(5,6,7,8-tetrahydro-1-naphthalenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 377 1.79 (b) 77

5-[(4-Amino-1-piperidinyl)methyl]- N-1,3-benzodioxol-5-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine 367 1.17 (b) 78

5-[(4-aminopiperidin-1-yl)methyl]- N-(3-chloro-4-methylphenyl)pyrro-lo[2,1-f][1,2,4]triazin-4-amine 371 1.793 79

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-chlorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 357 1.44 (b) 80

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-bromophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 401 1.56 (b) 81

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-bromo-3-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 419 1.68 (b) 82

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-bromo-3-methylphenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 415 1.85 (b) 83

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-propylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 365 1.98 (b) 84

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(1-methylethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 365 1.93 (b) 85

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(1,1-dimethylethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 379 2.21 (b)86

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(1,1-(trifluoromethyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 391 1.83(b) 87

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(trifluoromethoxy)phenyl]pyrrolo [2,1-f][1,2,4]triazin-4-amine 407 1.88(b) 88

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(1-methylethoxy)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 381 1.68 (b)89

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,4-dimethoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 383 1.09 (b) 90

1-[4-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4- yl]amino]phenyl]ethanone 365 1.44 (b) 91

5-[(4-Amino-1-piperidinyl)methyl]- N-(4-ethoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 367 1.44 (b) 92

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(difluoromethoxy)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 389 1.45(b) 93

4-[[5-[(4-Amino-1- piperidinyl)methyl]pYrrolo[2,1- f][1,2,4]triazin-4-yl]amino]benzamide 366 0.82 (b) 94

N-[4-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4- yl]amino]phenyl]acetamide. 380 1.04 (b) 95

2-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-4- methylbenzonitrile. 362 2.40 (b) 96

2-[[5-[(4-Amino-1- piperidinyl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]-4- chlorobenzonitrile. 382 2.55 (b) 100

5-[(4-Amino-1-piperidinyl)methyl]- N-[4-(4-morpholinyl)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 408 1.12 (b)102

5-[(4-Amino-1-piperidinyl)methyl]- N-(2,3-dihydro-1H-inden-5-yl)pyrrolo[2,1-fl [1,2,4]triazin-4- amine 363 1.78 (b) 103

3-[[5-[(4-Amino-1- piperidiyl)methyl]pyrrolo[2,1- f][1,2,4]triazin-4-yl]amino]benzonitrile, trifluoroacetic acid salt (1:1) 348 1.05 (a) 105

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 353 1.17 (a)106

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, trifluoroacetic acid salt (1:1) 357 1.25 (a)107

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-ethynylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 347 1.35 (a) 108

5-[(4-Amino-1-piperidinyl)methyl]- N-(3,4-dichlorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 391 1.91 (a) 109

5-[(4-Amino-1-piperidinyl)methyl]- N-(3-chlorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 357 0.75 (a) 110

5-[(4-aminopiperidin-1-yl)methyl]-N- (3-chloro-4-methoxyphenyl)pyrro-lo[2,1-f][1,2,4]triazin-4-amine 387 1.530 111

5-[(4-aminopiperidin-1-yl)methyl]- N-(3-bromo-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 401 1.560 112

5-[(4-aminopiperidin-1-yl)methyl]-N- (4-fluoro -phenyl)pyrrolo[2,1-]][1,2,4]triazin-4-amine 341 1.020 113

5-[(4-aminopiperidin-1-yl)methyl]-N- (2-methylphenyl)pyrrolo[2,1-[1,2,4]triazin-4-amine 337 1.030 114

5-[(4-aminopiperidin-1-yl)methyl]-N- (3-fluoro -phenyl)pyrrolo[2,1-1][1,2,4]triazin-4-amine 341 1.110 115

5-[(4-aminopiperidin-1-yl)methyl]-N- (4-methyl-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 337 1.310 116

5-[(4-aminopiperidin-1-yl)methyl]-N- (4-meth-oxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 353 1.170 117

5-({5-[(4-aminopiperi-din-1- yl)methyl]pyrro-lo[2,1-f][1,2,4]triazin-4-yl}amino)-2- fluoroben-zonitrile 366 1.103 118

5-[(4-aminopiperidin-1-yl)methyl]-N- (3-ethyn-yl-4-fluorophenyl)-pyrrolo[2,1 -1][1,2,4]tria-zin-4-amine 365 1.350 119

[3-({5-[(4-aminopiperi-din-1- yl)methyl]pyrro-lo[2,1-f][1,2,4]triazin-4- yl}amino)phenyl]methanol 353 0.837 120

5-[(4-aminopiperidin-1-yl)methyl]-N- (4-fluoro-3-methoxyphenyl)pyrro-lo[2,1-f][1,2,4]triazin-4-amine 371 1.162 121

5-[(4-aminopiperidin-1-yl)methyl]-N- [3-(difluo-romethoxy)phenyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine 389 1.370HPLC Conditions:

-   -   (a): (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over        4 minutes containing 0.2% H₃PO₄, 3 ml/min, monitoring at 220 nm)    -   (b): (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol        over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220        nm)        Note: Examples 97-99, 101 and 104 have been deleted from the        table as duplicates.

EXAMPLES 122 TO 132

Compounds 122 to 132 were prepared from Compound 1D,3-chloro-4-fluoro-phenylamine and corresponding amines or Boc protectedamines by a route analogous to that used for the preparation ofCompounds 38 to 121. HPLC [M + Ret Time Ex. R Compound Name H] (min) 122

5-[[(3S)-3-Amino-1- piperidinyl]methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine. 375 1.82 (b) 123

5-[[(3R)-3-Amino-1- piperidinyl]methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine. 375 1.83 (b) 124

1-[[4-[(3-Chloro-4- fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-(3R,4S)- rel-3,4-piperidinediol. 392 1.74(b) 125

N-(3-Chloro-4-fluorophenyl)-5-[(3,6- dihydro-1(2H)-pyridinyl)methyl]pyrrolo[2,1- f][1,2,4]triazin-4-amine. 358 2.12 (b) 126

5-[[(3R,4R)-rel-4-Amino-3-methyl-1- piperidinyl]methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, trifluoroacetic acidsalt (1:1). 389 1.71 (b) 127

5-[[(3R,4S)-rel-4-Amino-3-methyl-1- piperidinyl]methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, trifluoroacetic acidsalt (1:1). 389 1.557 (b) 128

4-[[4-[(3-Chloro-4- fluorophenyl) amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-(2S)-2- piperazinemethanol,trifluoroacetic acid salt (1:1). 391 1.97 (b) 129

5-[[(3R,4S)-4-Amino-3-methyl-1- piperidinyl]methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine 389 1.557 (b) 130

5-[[(3S,4R)-rel-4-Amino-3-methyl-1- piperidinyl]methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine, trifluoroacetic acidsalt (1:1). 389 1.557 (b) 131

N-(3-chloro-4-fluoro-phenyl)-5-{[4- (methyl-amino)piperidin-1-yl]-methyl}pyrrolo[2,1 j]-[1,2,4]triazin-4- amine 389 1.000^(a) 132

5-[(4-amino-4-methyl-piperidin-1- yl)methyl]-N-(3-chloro-4-fluoro-phenyl)pyrrolo[2,1-f-[1,2,4]triazin-4- amine 389 1.030^(a)

EXAMPLE 1335-[(4-Amino-1-piperazinyl)methyl]-N-(3-chloro-4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

133A. Preparation of(5-{[bis-(2-chloro-ethyl)-amino]-methyl}-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine

A mixture of Compound 1E (50 mg, 0.1 mmol), bis-(2-chloroethyl)aminehydrochloride (18 mg, 0.1 mmol), DIEA (36 μl, 0.2 mmol) in CH₃CN (0.5ml) was heated to 60° C. for 3 h. The mixture was cooled to rt andconcentrated to give Compound 133A which was used directly in next step.133A had an analytical HPLC retention time=2.986 min. (ChromolithSpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=416.

The crude 133A from the last step was taken into neat anhydrous N₂H₄(0.5 ml) and heated at 100° C. for several hours. The mixture was cooledto rt, diluted with H₂O and extracted with CH₂Cl₂. The combined extractswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by prep HPLC to give, after neutralization andextraction (with CH₂Cl₂), Compound 133 (38.8 mg, 100% for two steps).Analytical HPLC retention time=1.709 min. (Chromolith SpeedROD 4.6×50mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=376.

EXAMPLE 134(3-Chloro-4-fluoro-phenyl)-[5-(morpholin-2-ylmethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine

134A. Preparation of2-(4-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl)-morpholine-4-carboxylicacid tert-butyl ester

A solution of Compound 1A (1.0 g, 5.6 mmol) in CCl₄ (50 mL) was purgedwith nitrogen for one hour. Benzoyl peroxide (270 mg, 1.12 mmol) wasadded and the reaction mixture was heated to 86° C. N-bromosuccinimide(1.04 g, 5.88 mmol) was added in one portion. After 30 minutes, thereaction was cooled to room temperature and filtered. The filtrate wasconcentrated, re-dissolved in toluene (10 mL) and treated with2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (1.5 g,6.9 mmol). The solution was heated to 110° C. for eight hours, cooled toroom temperature and concentrated. Flash chromatography on silica (20%EtOAc/Hexanes) afforded the product as a light yellow oil thatcrystallized upon standing (770 mg, 32%). HPLC t_(R)=3.783 min (YMC S5ODS 4.6×50 mm, 10-90% aqueous methanol, 4 min gradient, monitored at 220nm). LC/MS (M+H)=178.

134B. Preparation of2-[4-(3-Chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl]-morpholine-4-carboxylicacid tert-butyl ester

A solution of2-(4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl)-morpholine-4-carboxylicacid tert-butyl ester (60 mg, 0.15 mmol) in CH₂Cl₂ (3 mL) was cooled to0 C and treated with a solution of mCPBA (56 mg, 0.32 mmol) in CH₂Cl₂ (2mL). The reaction was stirred for 15 minutes at 0 C then warmed to roomtemperature. To this solution was added 3-chloro-4-fluoroaniline andstirred at room temperature for one hour. The resulting orange solutionwas diluted with CH₂Cl₂ and washed with saturated aqueous NaHCO₃, thensaturated aqueous NaCl. The organic layer was dried (Na₂SO₄), filteredand concentrated. Preparative reverse-phase HPLC afforded the desiredcompound (30 mg, 41%). HPLC t_(R)=4.383 min (YMC S5 ODS 4.6×50 mm,10-90% aqueous methanol, 4 min gradient, monitored at 220 nm). LC/MS(M+H)=492.

A solution of 134B (30 mg, 0.06 mmol) in CH₂Cl₂ (3 mL) at 0° C. wastreated with trifluoroacetic acid (0.3 mL) dropwise. The reaction wasstirred for two hours then diluted with CH₂Cl₂ and washed with saturatedaqueous NaHCO₃. The organic layer was separated, dried (Na₂SO₄),filtered and concentrated. The crude compound was purified by radialchromatography (1 mm plate, 15% MeOH/CH₂Cl₂ to 30% MeOH/CH₂Cl₂) toafford Compound 134 (17 mg, 67%). HPLC t_(R)=2.83 min (YMC S5 ODS 4.6×50mm, 10-90% aqueous methanol, 4 min gradient, monitored at 220 nm). LC/MS(M+H)=392.

EXAMPLE 1354-Amino-1-[[4-[(3-chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-(3R,4R)-rel-3-piperidinol

To a solution of 1,2,3,6-tetrabydropyridine (1.66 g, 20.0 mmol) in dryCH₂Cl₂ (10 mL) was added triethyl amine (3.35 mL, 24.0 mmol), followedby a solution of N-(benzyloxycarbonyloxy)succinimide (5.23 g, 21.0 mmol)in dry CH₂Cl₂ (10 mL). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with CH₂Cl₂ (50mL) and washed with 10% citric acid, sat'd NaHCO₃, brine and dried overanhydrous Na₂SO₄. Concentration under reduced pressure afforded 4.34 gof Compound 135A: (100%) as an oil. Analytical HPLC retention time=2.996min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm).¹H-NMR (CDCl3): 7.20-7.35 (m, 5H), 5.88 (bs, 1H), 5.60-5.78 (m, 1H),5.18 (s, 2H), 3.99 (t, J=2.64, 2H), 3.59 (t, J=5.69, 2H), 2.18 (m, 2H).Compound 135B

To a solution of Compound 135A (1.1 g, 5.0 mmol) in dry CH₂Cl₂ (10 mL)cooled at 0° C. was added a solution of 75% m-CPBA (1.38 g, 6.0 mmol) indry CH₂Cl₂ (5 mL). The reaction mixture was stirred at 0° C. for 15 min,then at room temperature for 3 hrs. The reaction mixture was dilutedwith CH₂Cl₂ (20 mL) and washed with sat'd Na₂S2O₃, sat'd NaHCO₃, brineand dried over anhydrous Na₂SO₄. Concentration under reduced pressuregave 1.14 g (98%) of Compound 135B as an oil. Analytical HPLC retentiontime=2.279 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm). ¹H-NMR (CDCl₃): 7.20-7.36 (m, 5H), 5.05 (s, 2H), 3.80-3.96 (m, 1H),3.70 (m, 1H), 3.47 (m, 1H), 3.22 (bs, 1H), 3.07-3.20 (m, 2H)2.00 (m,1H), 1.87 (m, 1H).

Compounds 135C and 135D

To a solution of Compound 135B (233 mg, 1.0 mmol) in dry DMF (2 mL) wasadded a solution of sodium azide (100 mg, 1.5 mmol) in a 2:1 mixture ofacetone-water (2 mL). The reaction mixture was heated at 80° C.overnight. The solvents were removed under reduced pressure and theresidue was taken into EtOAc (20 mL), washed with water, 10% LiCl andbrine and dried over anhydrous Na₂SO₄-Concentration under reducedpressure gave an oil. Flash chromatography (hexane-ethyl acetate: 8:2 to7:3) on silica gel afforded 180 mg of Compound 135C (early eluent, amajor isomer) as an oil and 98 mg of Compound 135D (late eluent, minorisomer) as an oil.

Compound 135C

¹H-NMR (CDCl₃): 7.28-7.40 (m, 5H), 5.10 (s, 2H), 4.14 (dd, J1=4.03,J2==13.44, 1H), 4.02 (m, 1H), 3.50 (m, 1H), 3.38 (m, 1H), 3.00 (m, 1H),2.88 (m, 1H), 2.70 and 2.40 (partial m, 1H), 2.00 (m, 1H), 1.50 (m, 1H).

Compound 135D

¹H-NMR (CDCl₃): 7.20-7.35 (m, 5H), 5.06 (s, 2H), 4.25 and 4.10 (partialm, 1H), 3.99 (d, J=13.44, 1H), 3.50 (m, 1H), 3.22 (m, 1H), 2.85 (t,J=2.69, 1H), 2.73 (m, 1H), 2.40 (m, 1H), 1.90 (m, 1H), 1.45 (m, 1H).

Compound 135E

To a solution of Compound 135C (180 mg, 0.65 mmol) in THF (5 mL) wasadded water (0.05 mL) and triphenylphosphine (340 mg, 1.3 mmol) and thereaction mixture was heated to reflux for 6 hrs. After cooling to roomtemperature, EtOAc (20 mL) was added to the reaction mixture. Theorganic layers were extracted with 1.0 N HCl (10 mL×2) and combinedaqueous layers were back washed once with EtOAc (5 mL). 1.0 N NaOH wasadded to the aqueous layers to make it pH 10.0 and the mixture wasextracted with EtOAc (20 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄. Concentration under reduced pressure gave 165 mgof amine intermediate as a colorless oil.

To a solution of 165 mg of amine intermediate in dry CH₂Cl₂ (4 mL) wasadded triethylamine (0.11 mL, 0.78 mmol), followed by Boc2O (156 mg,0.72 mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was diluted with CH₂Cl₂ and washed with sat'd NaHCO₃and dried over anhydrous Na₂SO₄. Purification by flash chromatography(hexane-EtOAc: 9:1 to 8:2) on silica gel afforded 170 mg of Compound135E as a white solid. Analytical HPLC retention time=2.859 min.(Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) anda LC/MS M⁺+1=351⁺. ¹H-NMR (CDCl₃): 7.29-7.40 (m, 5H), 5.10 (s, 2H), 4.61(bs, 1H), 4.32 (bs, 1H), 3.90-4.30 (m, 1H), 3.30-3.60 (m, 2H), 2.80 (m,1H), 2.66 (m, 1H), 1.90 (m, 1H), 1.45 (s, 9H), 1.40 (m, 1H).

Compound 135F

A solution of Compound 135E (170 mg) in 5 mL of MeOH containing 10 mg ofPd(OH)₂ was stirred under hydrogen atmosphere (balloon) overnight. Thecatalyst was removed by filtration and rinsed with MeOH. The combinedfiltrates were concentrated under reduced pressure to give 138 mg ofCompound 135F as an oil. Analytical HPLC retention time=1.270 min.(Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 220 nm) anda LC/MS M⁺+1=217⁺.

Compound 135G

Compound 135G was prepared from Compound 135D in a similar procedure asCompound 135E. Analytical HPLC retention time=2.849 min. (ChromolithSpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFAover 4 minutes, 4 mL/min, monitoring at 254 nm). ¹H-NMR (CDCl₃):7.40-7.52 (m, 5H), 5.20 (s, 2H), 4.30 (m, 2H), 3.40 (m, 1H), 2.95 (m,1H), 2.67 (m, 2H), 2.08 (m, 1H), 1.45-1.96 (m, 3H), 1.45 (s, 9H).

Compound 135H

Compound 135H was prepared from Compound 135G in a similar procedure asCompound 135F. Analytical HPLC retention time=1.380 min. (ChromolithSpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFAover 4 minutes, 4 mL/min, monitoring at 220 nm).

Compound 135 was prepared in a similar manner as Example 1 usingCompound 135F and 1E. Compound 135 is a solid with an analytical HPLCretention time=1.666 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90%aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min,monitoring at 254 nm) and a LC/MS M⁺+1=391⁺. ¹H-NMR (CDCl₃): 11.62 (s,1H), 7.94 (s, 1H), 7.89 (dd, J_(1=2.60), J₂=6.61, 1H), 7.48 (d, J=2.60,1H), 7.45 (m, 1H), 7.15 (t, J=8.72, 1H), 6.51 (d, J=2.60, 1H), 3.82 (AB,J=13.60, □ν=26.94, 2H), 3.33 (m, 1H), 3.25 (m, 1H), 3.08 (d, J=12.09,1H), 2.57 (m, 1H), 2.22 (t, J=12.03, 1H), 2.05 (m, 1H), 1.97 (m, 1H),1.43 (m, 1H).

Alternatively, Compound 135 can be prepared as shown below.

Preparation of Compound 135J

Compound 135J was prepared according to a published literatureprocedure: Jacob Szmuszkovicz et al., Heterocycles, 1994, 39 (1),163-170.

Preparation of Compound 135K

Compound 135K was prepared according to a published literatureprocedure: Jacob Szmuszkovicz et al., Heterocycles, 1994, 39 (1),163-170.

Preparation of Compound 135L

Compound 135L was prepared from Compound 135K in a similar way asCompound 1C. Analytical HPLC retention time=2.323 min. (ChromolithSpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFAover 4 minutes, 4 mL/min, monitoring at 220 nm). ¹H-NMR (CDCl₃): 4.11(dd, J1=3.09, J2=13.29, 1H), 3.95 (m, 1H), 3.50 (m, 1H), 3.38 (m, 1H),2.90 (m, 1H), 2.79 (dd, J1=9.27, J2=13.29, 1H), 2.45 (m, 1H), 2.00 (m,1H), 1.55 (m, 1H), 1.46 (s, 9H).

Preparation of Compound 135M

To a solution of Compound 135L (0.6 g, 2.48 mmol) in dry CH₂Cl₂ cooledat 0° C., was added trifluoroacetic acid (5 mL). The reaction mixturewas stirred at 0° C. for 15 min, then warmed to room temperature andstirred for 3 hrs. The solvent and TFA were removed under reducedpressure and the residue was taken into CH₂Cl₂ (20 mL). The organiclayer was washed with sat'd NaHCO₃ and the aqueous layer wassupersaturated with solid NaCl, and back extracted with EtOAc (15mL×10). The combined organic extracts were dried over anhydrous Na2SO4.

Concentration in vacuo gave 350 mg of Compound 135M as an oil. ¹H-NMR(CDCl₃+CD₃OD): 3.55 (m, 1H), 3.43 (m, 1H), 3.18 (dd, J1=3.95, J2=12.63,1H), 3.07 (d of t, J1=12.90, J2=4.78, 1H), 2.74 (m, 1H), 2.63 (dd,J1=8.28, J2=12.58, 1H), 2.10 (m, 1H), 1.57 (m, 1H).

Preparation of Compound 135N

Compound 135N was prepared in a similar way as Compound 1F (using MethodTwo) in Example 1 starting from Compound 135M and 1E of Example 1.Compound 135N is a solid and has an analytical HPLC retention time=2.099min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) anda LC/MS M⁺+1=417⁺.

To a solution of above prepared Compound 135N (0.5 mmol) in a mixture ofTHF (5 mL) and water (0.05 mL) was added triphenylphosphine (262 mg, 1.0mmol). The reaction mixture was heated to reflux for 8 hrs. Aftercooling to room temperature, the solvent was evaporated under reducedpressure and the residue was directly purified by flash chromatography(CH₂Cl₂—MeOH-NH₄OH: 95:5:0.5) on silica gel to give 166 mg of Compound135 as a solid.

EXAMPLE 1363-Amino-1-[[4-[(3-chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-(3R,4R)-rel-4-piperidinol

Compound 136 was prepared in a similar manner as Example 1 usingCompound 135H and 1E. Compound 136 is a solid, with an analytical HPLCretention time=1.953 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90%aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min,monitoring at 254 nm) and a LC/MS M⁺+1=391⁺.

EXAMPLE 1374-Amino-1-[[4-[(3-chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-(3R,4R)-(+)-rel-3-piperidinol

and EXAMPLE 1384-Amino-1-[[4-[(3-chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-(3R,4R)-(−)-rel-3-piperidinol

The racemic Compound 135 was resolved using a normal phase chiralpreparative HPLC (Chiralpak AD) using hexane-isopropylalcohol-diethylamine (80:20:0.05) as mobil phase. Compound 137(Eanatiomer A) and Compound 138 (Enantiomer B) were obtained as singleenantiomers with >99% ee.

EXAMPLE 139N-(3-Chloro-4-fluorophenyl)-5-[[4-[(2,2-dimethylpropyl)amino]-1-piperidinyl]methyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of the compound of Example 1 (19 mg, 0.05 mmol) in CH₂Cl₂(1 mL) was added glacial acidic acid (0.05 mL), followed by3,3-dimethylbutyraldehyde (0.008 mL, 0.073 mmol) and sodiumtriacetoxyborohydride (25 mg, 0.12 mol). The mixture was stirred at roomtemperature for 30 hrs. The reaction mixture was diluted with CH₂Cl₂,washed with water, sat'd NaHCO₃, brine and dried over anhydrous Na₂SO₄.Concentration in vacuo followed by flash chromatography(CH₂Cl₂-MeOH-NH₄OH: 98:2:0.2 to 98:5:0.5) on silica gel gave Compound139 as an oil. Analytical HPLC retention time=1.976 min. (ChromolithSpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFAover 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M⁺+1=445⁺.

EXAMPLE 140N-(3-Chloro-4-fluorophenyl)-5-[[4-(propylamino)-1-piperidinyl]methyl]-pyrrolo[2,1-f][1,2,4]triazin-4-amine

Compound 140 was prepared in a similar way as Compound 139 fromCompound 1. Compound 140 is a solid and has an analytical HPLC retentiontime=1.689 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=417⁺.

EXAMPLE 1411-[[4-[(3-Chloro-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-4-piperidinol

Compound 141 was prepared in a similar way as Compound 1 from 1E ofExample 1. Compound 141 is a solid and had an analytical HPLC retentiontime=1.803 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=376⁺.

EXAMPLE 142trans-4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-cyclohexanol

A. Preparation of 4-Chloro-pyrrolo[2,1-f][1,2,4]triazine-5-carbaldehyde

A solution of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (1.68 g,10 m mole) in CCl₄ was sparged with N₂ for 20 min and then NBS (3.74 g,21 mmole) followed by benzoyl peroxide (242 mg, 1 mmole) were added. Thereaction mixture was put into a 100° C. oil bath and refluxed for 3 h.After cooling to RT, this was filtered and the solvent removed. Theresidue was suspended in CH₃OH (100 ml) and solid NaHCO₃ (5 g) wasadded. The reaction mixture was stirred vigorously for 1 h, filtered,and the solvent removed. The residue oil was resuspended in DCM,filtered, and concentrated to afford the crude dimethyl acetal which wastreated with DCM (20 ml)/H₂O (20 ml)/TFA (1 ml). After stirringvigorously for 1.5 hours, this was neutralized with aqueous saturatedNaHCO₃ and extracted with DCM. The combined extracts were dried(Na₂SO₄), concentrated and chromatographed (3×15 cm silica gel columneluted with DCM) to afford the title compound (1.02 g, 56%) as a solid.MS: 182 (M+H)⁺; HPLC Ret Time: 0.79 min (Xterra 3.0×50 mm S7 column, 2min gradient, 5 mL/min).

B. Preparation of[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-chloro-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-methanol

A solution of trans-4-tertbutyldimethylsilyoxy-cyclohexylmagnesiumbromide (Bioorg. and Med. Chem., 1996, 6, 201) in THF (4 equiv) wasadded slowly to an ice-cooled solution of4-chloro-pyrrolo[2,1-f][1,2,4]triazine-5-carbaldehyde (1.05 g, 5.8mmole) in THF (15 mL). After 1 h, a saturated aqueous solution of NH₄Cl(15 mL) was added and the aqueous layer was extracted with EtOAc/hexane(1:1) (50 mL×2). The combined organic extracts were dried over Na₂SO₄and concentrated in vacuo. The crude material was purified via radialchromatography (4 mm silica gel plate, gradient elution with 0 to 15%EtOAc in DCM) to afford the title compound: 189 mg of cis-isomer, 496 mgof tran-isomer and 415 mg of mixture (total yield 48%, the ratio ofcis:trans is about 1:4). cis-isomer: MS: 396 (M+H)⁺; HPLC Ret Time: 2.10min (Xterra 3.0×50 mm S7 column, 2 min gradient, 5 mL/min);trans-isomer: MS: 396 (M+H)+; HPLC Ret Time 2.08 min (Xterra 3.0×50 mmS7 column, 2 min gradient, 5 mL/min).

C. Preparation of [4-(3-Chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-[4-(1-methyl-1-trimethylsilanyl-ethoxy)-cyclohexyl]-methanol

A mixture oftrans-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-(4-chloro-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-methanol(840 mg, 2.13 mmole), 3-chloro-4-fluoro-phenylamine (309 mg, 2.13 mmole)and NaHCO₃ (536 mg, 6.39 mmole) in CH₃CN (10 mL) was heated at 70° C.overnight. The solvent was removed and the residue was suspended in DCM,washed with water, and dried over Na₂SO₄. Removal of the solventfollowed by radial chromatography (4 mm silica gel plate, gradientelution with 0 to 2% NH₃ in MeOH (2N) in DCM) afforded the titlecompound (612 mg, 57%) as a solid: MS: 506 (M+H)⁺; HPLC Ret Time: 2.29min (Xterra 3.0×50 mm S7 column, 2 min gradient, 5 mL/min).

D. Preparation oftrans-4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-cyclohexanol

A mixture of [4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-[4-(1-methyl-1-trimethylsilanyl-ethoxy)-cyclohexyl]-methanol(448 mg, 0.887 mmole) triethylsilane (1.03 g, 8.87 mmole) in TFA (8 mL)under N₂ in a pressure flask was heated at 75° C. overnight. Thesolvents were removed and the residue was dissolved in CH₃OH (10 ml) andsolid Na₂CO₃ (2.0 g) was added. After stirring vigorously for 1 h, thesolvent was removed and the residue was partitioned between DCM (200 ml)and H₂O (50 ml). The organic phase was separated, dried over Na₂SO₄, andthe solvent was removed. Purification via radial chromatography (2 mmsilica gel plate, gradient elution with 0 to 4% NH₃ in MeOH (2N) in DCM)afforded the title compound (209 mg, 63%) as a solid: MS: 375 (M+H)⁺;HPLC Ret Time: 1.49 min (Xterra 3.0×50 mm S7 column, 2 min gradient, 5mL/min).

EXAMPLE 143cis-4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-cyclohexanol

Similarly, the title compound was prepared fromcis-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-(4-chloro-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-methanol:375 (M+H)⁺; HPLC Ret Time: 1.56 min (Xterra 3.0×50 mm S7 column, 2 mingradient, 5 mL/min).

EXAMPLE 1444-[4-(3-Chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-cyclohexanone

A solution ofcis-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-(4-chloro-pyrrolo[2,1-f][1,2,4]triazin-5-yl)-methanol:(53 mg, 0.14 m mole), 4-methylmorpholine N-oxide (25 mg, 0.21 mmole),TPAP (5 mg, 0.1 eq) and powered 4A molecular sieves (100 mg) in DCM (3ml) under N₂ was stirred at RT. After 5 h, this was filtered and thesolvent removed. Radial chromatography (1 mm silica gel plate, gradientelution with 0 to 5% NH₃ in MeOH (2 N) in DCM) afforded the titlecompound (25 mg, 47%) as a solid: MS: 373 (M+H)⁺; HPLC Ret Time: 1.50min (Xterra 3.0×50 mm S7 column, 2 min gradient, 5 mL/min).

EXAMPLE 1454-Amino-1-[4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-cyclohexanol

To a solution of4-[4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-4-hydroxy-cyclohexanone(24 mg, 0.06 mmole) in dry MeOH (0.5 mL) was added powdered 3A molecularsieves (24 mg), (10 eq) NH₄OAc (48 mg, 0.06 mmole), and NaCNBH₃ (4 mg,0.06 mmole); the reaction stirred under nitrogen for 12 hr. The reactionmixture was filtered and a 15% NaOH solution was added. After 10 min,the mixture was diluted with DCM (50 mL) and washed with water. Theorganic phase was dried (Na₂SO₄) and the solvent was removed. Thematerial was purified and separated by preparative HPLC to afford thetitle compound (3.5 mg, 15%) and the cis isomer (7.9 mg, 32%). The titlecompound: MS: 390 (M+H)⁺; HPLC Ret Time: 2.070 min (XTERRA 4.6×50 mm S5column, 3 min gradient, 4 mL/min). The cis isomer: MS: 390 (M+H)⁺; HPLCRet Time: 2.190 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4mL/min).

EXAMPLE 146(3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol

Preparation of Compounds 146A and 146B(3R,4R)-4-Azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(146A)

(3S,4S)-4-Azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(146B)

Compounds 146A and 146B were obtained from Compound 135L by opticalresolution using a normal phase chiral preparative HPLC (Chiralpak AD)using MeOH-EtOH (50:50) as mobil phase. Compound 146A (first eluent) andCompound 146B (second eluent) were obtained as single enantiomerswith >99% ee. The absolute stereochemistry of Compound 146A (3R, 4R) wasdetermined by a single X-ray crystallographic analysis.

Preparation of Compound 146C

To a solution of Compound 146A (1.76 g, 7.26 mmol) in dry CH₂Cl₂ (15 mL)cooled at 0° C., was added trifluoroacetic acid (10 mL). The reactionmixture was stirred at 0° C. for 15 min, then warmed to room temperatureand stirred for 3 hrs. The solvent and TFA were removed under reducedpressure and the residue was azeotropically evaporated several timeswith CH₂Cl₂ to give Compound 146C as a TFA salt.

Preparation of Compound 146D

Compound 146D was prepared, as a TFA salt, in a similar manner asCompound 146C using Compound 146B.

Preparation of Compound 146E

Compound 146E was prepared in a similar way as Example 105 (using MethodOne) replacing Compound 146C for piperidin-4-yl-carbamic acid tert-butylester. Compound 146E is a solid and has an analytical HPLC retentiontime=2.019 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=395⁺.

Compound 146 was prepared from Compound 146E in a similar way asCompound 135. Compound 146 is a solid, with an analytical HPLC retentiontime=1.213 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=369⁺. The enantiomeric excess (ee) of Compound 146is >99% (Chiralpak AD, 250×4.6 mm 10 micron, EtOH-MeOH-Et2NH:50:50:0.1).

Alternate Preparation of Compound 146 Preparation of Compound 146F

To a solution of 1-methyl-1,2,3,6-tetrahydropiperidine HCl salt (227 g)in 570 mL of water was added solid K₂CO₃ (235 g) and the mixture wasstirred at room temperature for 30 min. The mixture was extracted withtoluene (500 mL×3) and combined extracts were dried over anhydrousMgSO₄. Filtration to remove MgSO₄ and the filtrate was placed in a 3-Lthree-necked RB flask. K₂CO₃ (22.7 g) was added to the filtrate and themixture was heated to gentle reflux (bath temperature 110° C.). Ethylchloroformate (318 mL) was added slowly over 2.5 hrs via an additionalfunnel (the reaction is extremely exothermic so slow addition withmagnetic stirring is highly recommended). Upon completion of addition,the mixture was refluxed for an additional 2.0 hrs and cooled to roomtemperature. The reaction mixture was washed with water, brine and driedover anhydrous MgSO₄. Filtration and concentration in vacuo afforded188.6 g (72%) of Compound 146F as an oil. ¹H-NMR (400 MHz, CDCl₃):

Preparation of Compound 146G (racemic)

To a solution of Compound 146F (178.2 g, 1.15 mol) in 2 L of dry CH₂Cl₂at 0° C. was added solid m-CPBA (386 g, 1.72 mol, 77% max) in smallportions. The reaction mixture was stirred for 1.0 hr at 0° C. and thenovernight at room temperature. The precipitate was removed by filtrationand the filtration cake was rinsed with CH₂Cl₂. The combined filtrateand washes were washed with 20% Na₂S₂O₃ (3 L×3), saturated NaHCO₃ (3L×3) and dried over anhydrous Na₂SO₄. Filtration followed byconcentration in vacuo afforded 170 g of Compound 146G as an oil. Thismaterial was used directly in the next reaction step without furtherpurification.

Preparation of Compound 146H (Chiral)

The mixture of Compound 146G (140 g, 0.818 mol), NaN₃ (68.9 g, 1.06 mol)and NH₄Cl (56.7 g, 1.06 mol) in ethanol (600 mL) and water (150 mL) washeated at 70° C. overnight. Upon cooling to room temperature, the solidwas removed by filtration and rinsed with ethanol. The combinedfiltrates were concentrated in vacuo to small volume (ca. 80 mL), thendiluted with water (500 mL) and extracted with EtOAc (500 mL×4). Thecombined extracts were dried over anhydrous Na₂SO₄. Filtration followedby concentration in vacuo and purification by flash chromatography(hexane-EtOAc 7:3 to 6:4) on silica gel afforded Compound 146G infollowing fractions: 80.7 g of first fraction (AP: >98%), 22.7 g ofsecond fraction (AP: 92-95%) and 15.8 g of third fraction (AP: <60%) asan oil. This material was used directly in next step reaction withoutfurther purification. The first and second fractions were combined andsubjected to optical resolution using chiral preparatory HPLC withfollowing conditions: Chiralpak AD column, eluted with MeOH-EtOH (1:1).The first eluted peak (Rt=5.605 min) was collected to give 47.52 g ofCompound 146H, with >99% ee.

Preparation of Compound 1461 (Chiral)

To a solution of Compound 146H (36.42 g, 0.17 mol) in 480 mL of EtOH wasadded a solution of KOH (112 g, 1.7 mol, 85%) in 240 mL of water. Themixture was heated to reflux for 9.0 hrs and the reaction progress wasmonitored by TLC. Upon cooling to room temperature, the mixture wasconcentrated in vacuo to give a paste. Solid NaCl was added and themixture was extracted with EtOAc (500 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄. Filtration followed by removal ofsolvent under reduced pressure afforded 23 g (77%) of crude Compound146I as a solid. Trituration with ether (250 mL) gave 18.53 g ofCompound 146I as a solid (AP: 99%). The mother liquid was concentratedin vacuo, solid NaCl was added and further extracted with more EtOAc(250 mL×4) to provide an additional 4.2 g of crude Compound 146I (AP:<85%).

Compound 146 was prepared from Compound 146I following the procedureused for the preparation of Compound 146E.

EXAMPLE 147(3S,4S)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]3-piperidin-3-ol

Preparation of Compound 147A

Compound 147A was prepared in a similar way as Example 105 (using MethodOne) replacing Compound 130D for piperidin-4-yl-carbamic acid tert-butylester. Compound 147A is a solid and had an analytical HPLC retentiontime=? min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=395⁺.

Compound 147 was prepared from Compound 147A in a similar way asCompound 135. Compound 147 is a solid, with an analytical HPLC retentiontime=1.213 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=369⁺. The enantiomeric excess (ee) of Compound 147is >99% (Chiralpak AD, 250×4.6 mm 10 micron, EtOH-MeOH-Et2NH:50:50:0.1).

EXAMPLE 148(3R,4R)-4-amino-1-[[4-[(3-methoxy-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol

Compound 148 was prepared from Compound 146C in a similar way asCompound 135. Compound 148 is a solid, with an analytical HPLC retentiontime=1.187 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=387⁺. The enantiomeric excess (ee) of Compound 148is >99% (Chiralpak AD, 250×4.6 mm 10 micron, EtOH-MeOH-Et2NH:50:50:0.1).

EXAMPLE 149(3S,4S)-4-amino-1-[[4-[(3-methoxy-4-fluorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-piperidin-3-ol

Compound 149 was prepared from Compound 146D in a similar way asCompound 135. Compound 149 is a solid, with an analytical HPLC retentiontime=1.187 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254nm) and a LC/MS M⁺+1=387⁺. The enantiomeric excess (ee) of Compound 149is >99% (Chiralpak AD, 250×4.6 mm 10 micron, EtOH-MeOH-Et2NH:50:50:0.1).

EXAMPLES 150 TO 200

Compounds 150 to 200 (with HPLC note (b)) were similarly prepared from146I as Compound 146.

HPLC [M + Ret Time Ex. R Compound Name H] (min) 150

(3R,4R)-4-amino-1-({4-[(3- chlorophenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol 373 1.508 151

3-[(5-{[(3R,4R)-4-amino-3- hydroxypiperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]benzonitrile 364 1.348 152

(3R,4R)-4-amino-1-({4-[(4-fluoro-3- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 371 1.542 153

(3R,4R)-4-amino-1-[(4-{[3- (difluoromethoxy) phenyl]amino}pyrrolo[2,1-]][1,2,4]triazin- 5-yl)-methyl]piperidin-3-ol 405 1.610 154

(3R,4R)-4-amino-1-({4-[(3-ethynylphenyl)- amino]pyrrolo[2,1j]-[1,2,4]-triazin-5-yl}- methyl)piperidin-3-ol 363 1.730 155

(3R,4R)-4-amino-1-({4-[(2-chloro-5- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 403 1.300 156

(3R,4R)-4-amino-1-({4-[(4-chloro-3- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 403 1.620 157

(3R,4R)-4-amino-1-({4-[(3-ethoxyphenyl)- amino]-pyrrolo[2,1j]-[1,2,4]triazin-5-yl}- methyl)piperidin-3-ol 383 1.540 158

(3R,4R)-4-amino-1-({4-[(3- isopropoxyphenyl)-amino]pyrrolo[2,1-1][1,2,4]triazin-5-yl}methyl-)-piperidin-3-ol 397 1.820 159

(3R,4R)-4-amino-1-[(4-{[3- (trifluoromethyl)- phenyl]amino}pyrrolo[2,1-1][1,2,4]triazin- 5-yl)-methyl]piperidin-3-ol 407 1.110^(b)160

(3R,4R)-4-amino-1-({4-[(3-methylphenyl)-amino]pyrrolo[2,1-1][1,2,4]triazin-5-yl}- methyl)piperidin-3-ol 3531.410 161

(3R,4R)-4-amino-1-[(4-anilinopyrrolo[2,1--[1,2,4]triazin-5-yl)-methyl]piperidin-3-ol 339 0.580^(b) 162

(3R,4R)-4-amino-1-({4-[(2-fluoro-5- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.283 163

(3R,4R)-4-amino-1-({4-[(4-fluorophenyl)-amino]pyrrolo[2,1-1][1,2,4]triazin-5-yl}- methyl)piperidin-3-ol 3570.820^(a) 164

(3R,4R)-4-amino-1-{[4-(2-naphthylamino)-pyrrolo[2,1-1][1,2,4]-triazin-5-yl]methyl}- piperidin-3-ol 389 1.130^(a)165

(3R,4R)-4-amino-1-({4-[(5-bromo-2-fluoro-phenyl)amino]pyrrolo[2,1-]][1,2,4]triazin- 5-yl}-methyl)piperidin-3-ol435 2.100 166

(3R,4R)-4-amino-1-({4-[(3,4- dichlorophenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 407 1.260^(a) 167

(3R,4R)-4-amino-1-( {4-[(4-bromophenyl)-amino]pyrrolo[2,1-1][1,2,4]triazin-5-yl}- methyl)piperidin-3-ol 4191.310^(a) 168

(3R,4R)-4-amino-1-({4-[(4-bromo-3- chloro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 453 1.670^(a) 169

(3R,4R)-4-amino-1-({4-[(3,4- dimethylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 367 1.200^(a) 170

(3R,4R)-4-amino-1-({4-[(3-chloro-4- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.460^(a) 171

N-{3-[(5-{[(3R,4R)-4-amino-3-hydroxy-piperidin-1-yl]methyl}-pyrrolo[2,1- f][1,2,4]triazin-4-yl)amino]-phenyl}acetamide 396 0.900^(a) 172

(3R,4R)-4-amino-1-({4-[(4-methylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}- methyl)piperidin-3-ol 3531.040^(a) 173

(3R,4R)-4-amino-1-({4-[(3- fluorophenyl)amino]pyrrolo[2,1-f[1,2,4]triazin-5-yl}methyl)-piperidin-3-ol 357 0.870^(a)174

(3R,4R)-4-amino-1-({4-[(3-methoxy-4- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 383 1.160^(a) 175

(3R,4R)-4-amino-1-({4-[(2-fluoro-5- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 371 1.120^(a) 176

(3R,4R)-4-amino-1-{[4-({3- [(trifluoromethyl)- thio]phenyl}amino)pyrrolo[2,1- f][1,2,4]triazin-5-yl]methyl}piperidin-3-ol 4391.770^(a) 177

(3R,4R)-4-amino-1-({4-[(3,4- difluorophenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl-methyl)-piperidin-3-ol 375 1.080^(a) 178

(3R,4R)-4-amino-1-[(4-{[4-fluoro-3- (trifluoro-methyl)phenyl]amino}pyrrolo[2,1-f][1,2,4]-tria-zin-5-yl)methyl]piperi-din-3-ol 425 1.230^(a) 179

(3R,4R)-4-amino-1-({4-[(4-bromo-3-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin- 5-yl}-methyl)piperidin-3-ol435 1.480^(a) 180

(3R,4R)-4-amino-1-({4-[(4-chloro-3- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.430^(a) 181

(3R,4R)-4-amino-1-({4-[(3-fluoro-4- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 371 1.240^(a) 182

(3R,4R)-4-amino-1-({4-[(2,3- difluorophenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)-piperidin-3-ol 375 0.880^(a) 183

(3R,4R)-4-amino-1-({4-[(4-bromo-3- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 431 1.520^(a) 184

(3R,4R)-4-amino-1-({4-[(3- bromophenyl)amino ]pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-ol 419 1.260^(a) 185

(3R,4R)-4-amino-1-({4-[(5-chloro-2-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin- 5-yl}-methyl)piperidin-3-ol391 1.060^(a) 186

(3R,4R)-4-amino-1-[(4-{[2-fluoro-5- (trifluoro-methyl)phenyl]amino}pyrrolo[2,1-f][1,2,4]tria-zin-5-yl)methyl]piperi-din-3-ol 425 1.200^(a) 187

(3R,4R)-4-amino-1-({4-[(3,5- difluorophenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)-piperidin-3-ol 375 1.120^(a) 188

(3R,4R)-4-amino-1-[(4-{[3- (methylthio)phenyl]amino}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-methyl]piperidin-3-ol 385 1.200^(a)189

(3R,4R)-4-amino-1-({4-[(3- ethylphenyl)amino]pyrrolo[2,1-f][1,2,4]tria-zin-5-yl}methyl)piperi-din-3-ol 367 1.870^(a) 190

(3R,4R)-4-amino-1-({4-[(4-fluoro-3- hydroxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 373 0.876 191

(3R,4R)-4-amino-1-({4-[(3- hydroxyphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl )piperidin-3-ol 355 0.915 192

(3R,4R)-4-amino-1-({4-[(4-hydroxy-3- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl }-methyl)piperidin-3-ol 385 0.850 193

(3R,4R)-4-amino-1-({4-[(3-chloro-5- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.717 194

(3R,4R)-4-amino-1-({4-[(3-fluoro-5- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.346 195

(3R,4R)-4-amino-1-{[4-(quinolin-6-ylamino)-pyrrolo[2,1-f][1,2,4]tria-zin-5- yl]methyl}piperi-din-3-ol 3900.870 196

(3R,4R)-4-amino-1-({4-[(3-bromo-5- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 447 1.709 197

(3R,4R)-4-amino-1-[(4-{[3- (trifluoromethoxy)- phenyl]amino}pyrrolo[2,1-f][1,2,4]triazin- 5-yl)-methyl]piperidin-3-ol 423 1.200^(b)198

(3R,4R)-4-amino-1-{[4-(1,3-benzothiazol-6-yl-amino)pyrrolo[2,1-f][1,2,4]triazin-5- yl]methyl }piperidin-3-ol 3960.840^(a) 199

{3-[(5-{[(3R,4R)-4-amino-3-hydroxypiperi- din-1-yl]methyl}pyrro-lo[2,1-f][1,2,4]triazin-4-yl)amino]phenyl}aceto- nitrile 378 0.790^(a) 200

(3R,4R)-4-amino-1-[(4-{[3-(1,3-oxazol-5- yl)-phenyl]amino}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-methyl]piperidin-3-ol 406 0.910^(a)^(a)2 min gradient time for HPLC. ^(b)2 min gradient time for HPLC(Phenom-prime S5 C18 4.6×30 mm column.

EXAMPLE 201rac-(3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol

201A. Preparation of (±)-tert-butyl4-azido-3-oxopiperidine-1-carboxylate

Anhydrous DMSO (0.28 mL, 3.79 mmol) was added to a stirred solution ofoxalyl chloride (0.172 mL, 1.96 mmol) in 6 mL of dry CH₂Cl₂ at −78° C.under argon. After 10 min, a solution of Compound 135L (396 mg, 1.63mmol) in 4.5 mL of dry CH₂Cl₂ was added dropwise, and the reactionmixture was stirred at −78° C. for 30 min. Triethylamine (1.38 mL, 10.0mmol) was added and the reaction mixture was allowed to warm to roomtemperature. 2.0 mL of pH 7.0 buffer solution was added and the mixturewas extracted with CH₂Cl₂ (×3). The combined organic layers were washedwith brine and dried over anhydrous Na₂SO₄. Concentration in vacuoafforded crude 201A as an oil which was used immediately in the nextreaction step.

¹H-NMR (400 MHz, CDCl₃): 4.30 (d, J=17.84, 1H), 4.05 (m, 1H), 3.90-4.00(m 1H), 3.45 (m, 1H), 2.85 (m, 1H), 2.33 (m, 1H), 1.86 (m, 1H), 1.47 (s,9H).

201B. Preparation of (±)-tert-butyl4-azido-3-hydroxypiperidine-1-carboxylate

To a solution of Compound 201A prepared above in dry THF (2 mL) cooledat −78° C. was added L-Selectride (1.0 M in THF, 0.98 mL, 0.98 mmol).The mixture was stirred at −78° C. for 2.0 hrs. Saturated NH₄Cl (2 mL)was added and the reaction mixture was allowed to warm to roomtemperature. The mixture was diluted with water and extracted with EtOAc(3×). The combined organic layers were washed once with brine and driedover anhydrous Na₂SO₄. Concentration in vacuo followed by flashchromatography (hexane-EtOAc 4:1) on silica gel gave 44 mg of Compound201B as an oil. ¹H-NMR (400 mHz, CDCl₃): 3.84 (m, 1H), 3.69 (m, 1H),3.58 (m, 2H), 3.40 (m, 1H), 3.30 (m, 1H), 1.96 (m, 1H), 1.73 (m, 1H),1.46 (s, 9H).

201C. Preparation of (±)-4-azidopiperidin-3-ol

Compound 201B (44 mg, 0.18 mmol) was treated with a mixture of CH₂Cl₂and TFA (1:1, 2 mL) for 30 min. The volatiles were removed under reducedpressure and the residue was azeotropically evaporated withheptane-CH₂Cl₂ three times to give a TFA salt of Compound 201C, whichwas used immediately in the next reaction without step furtherpurification.

Preparation of 201D

Compounds 201D was prepared as a solid from Compound 201C in a similarway as Compound 146E. It had an analytical HPLC retention time=1.795min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺=395.

Compound 201 was prepared from Compound 201D in a similar way asCompound 146. It had an analytical HPLC retention time=1.169 min.(Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺=369.

EXAMPLE 202A AND 202B(3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-][1,2,4]triazin-5-yl}methyl)piperidin-3-ol(Enantiomer A, chiral)

and

(3R,4S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol(Enantiomer B, chiral)

Compound 202A (15 mg) and compound 202B (15 mg) were obtained by opticalresolution of Compound 201 (30 mg) using the following method: ChiralpakAD chiral preparatory column eluted with hexane-isopropylalcohol-diethylamine (50:50:0.1) using gradient of 6.0 ml/min flow rateand detected at 220 nm. The first eluted peak corresponds to Compound202A (retention time=4.337 min) with ee % ≧98%; the second eluted peakcorresponds to Compound 202B (retention time=6.050 min) with ee % ≧98%.

EXAMPLE 203(3S,4R)-4-amino-1-({4-[(3-methylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ol(chiral)

Preparation of Compound 203A and 203B (Chiral)

To a solution of Compound 146G (100 g, 0.585 mol) in 2 L of chloroformcooled at −60° C. was added, dropwise via an additional funnel, 196.5 mLof 48% HBr while the internal temperature was kept below −60° C. Uponcompletion of addition, the reaction mixture was stirred for another 1.0hr at −60° C. The reaction mixture was warmed to room temperature andwashed with water (1 L×2), brine (1 L) and dried over anhydrous MgSO4.Filtration followed by concentration in vacuo afforded 134.2 g (91%) ofcrude compound (racemic mixture of 203A and 203B) as an oil.

¹H-NMR (400 MHz, CDCl₃): 4.25 (m, 1H), 4.15 (q, J=7.10, 2H), 4.00 (m,1H), 3.90 (bs, 1H), 3.75 (m, 1H), 2.85-3.15 (m, 2H), 2.32 (m, 1H), 2.00(m, 1H), 1.28 (t, J=7.10, 3H).

Compounds 203A and 203B were obtained from optical resolution of theabove racemic mixture by a normal phase chiral preparative HPLC(Chirlapak AD) using CH₃CN as a mobil phase. 54.77 g of Compound 203B(first eluent, Rt=5.861 min) and 53.71 g of Compound 203A (secondeluent, Rt=8.719 min) were obtained as single enantiomers with >99% ee.The absolute stereochemistry of Compound 203B (3R, 4S) was assignedbased on the a single x-ray crystallographic analysis of Compound 203.

Preparation of Compound 203C (Chiral)

To a solution of Compound 203A (53.7 g, 0.213 mol) in 250 mL of DMF, wasadded imidazole (21.8 g, 0.32 mol), followed by t-butyldimethylsilylchloride (38.5 g, 0.258 mol) at 0° C. The reaction mixture was stirredat ambient temperature overnight. Ether (1 L) was added to the reactionmixture, followed by water (1 L) at 0° C. The organic layer wasseparated. The aqueous layer was extracted with ether (1 L×2) andcombined organic layers were washed with 10% LiCl (750 mL×3), dried overanhydrous MgSO₄. Filtration followed by concentration in vacuo affordedcrude Compound 203C as an oil, which was used immediately withoutfurther purification.

Preparation of Compound 203D (Chiral)

Compound 203D was prepared from Compound 203B in a similar way asCompound 203C.

Preparation of Compound 203E (Chiral)

To a solution of Compound 203C (0.213 mol) in 300 mL of DMSO was addedNaN₃ (15.3 g, 0.234 mol) and the mixture was heated at 85° C. for 12hrs. Additional NaN₃ (15.0 g, 0.230 mol) was added and the reactionmixture was heated overnight. Upon cooling to room temperature, icewater was added to the reaction mixture and extracted with ether (1L×3). The combined organic layers were washed once with brine (1 L) anddried over anhydrous MgSO₄. Filtration followed by concentration invacuo afforded 69.5 g of crude Compound 203E as an oil, which was usedimmediately without further purification.

Preparation of Compound 203F (Chiral)

Compound 203F was prepared from Compound 203D in a similar way asCompound 203E.

Preparation of Compound 203G (Chiral)

The mixture of Compound 203E (0.213 mol) prepared above and TBAF.xH₂O(67 g, 0.255 mol) in 200 mL of THF was stirred at room temperature for3.0 hrs. Ether (1 L) was added and the mixture was washed with water (1L). The aqueous phase was extracted with ether (1 L×2). The combinedorganic layers were washed once with water (1 L) and dried overanhydrous MgSO₄. Concentration in vacuo followed by flash chromatography(CH₂Cl₂-EtOAc: 4:1) on silica gel afforded 29.8 g of Compound 203G as anoil. Second flash chromatography (hexane-EtOAc: 6.5:3.5) on silica gelgave 20 g (44%) of Compound 203G as an oil. ¹H-NMR (400 MHz, CDCl₃):4.15 (q, J=7.10, 2H), 3.86 (bs, 1H), 3.70 (bs, 1H), 3.65 (m, 1H), 3.47(dd, J=3.20, J=13.62, 1H), 3.35 (m, 1H), 2.02 (m, 1H), 1.79 (bs, 1H),1.28 (t, J=7.10, 3H).

Preparation of Compound 203H (Chiral)

Compound 203H was prepared from Compound 203F in a similar way asCompound 203G.

Preparation of Compound 203I (Chiral)

Compound 203I was prepared from Compound 203G in a similar way asCompound 146I. Compound 203I is a solid with ≧99ee %. ¹H-NMR (400 MHz,CDCl₃): 3.80 (m, 1H), 3.44 (m, 1H), 3.04 (m, 2H), 2.72 (m, 1H), 2.69 (m,1H), 1.90 (m, 1H), 1.75 (m, 1H).

Preparation of Compound 203J (Chiral)

Compound 203J was prepared from Compound 203H in a similar way asCompound 146I. Compound 203J is a solid with ≧99ee %.

Compound 203 was prepared from Compound 1B, meta-methylaniline andCompound 203I in a similar way as Compound 146. It had an analyticalHPLC retention time=1.278 min. (Chromolith SpeedROD 4.6×50 mm column,10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min,monitoring at 220 nm) and a LC/MS M⁺+1=353.

EXAMPLES 204 TO 211

Compounds 204 to 211 (with HPLC note (b)) were similarly prepared fromCompound 1B, the corresponding anilines and Compound 2031, as used forCompound 146.

HPLC [M + Ret Time Ex. R Compound Name H] (min) 204

(3S,4R)-4-amino-1-({4-[(3- chlorophenyl)amino]-pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-ol 373 1.356 205

3-[(5-{[(3S,4R)-4-amino-3-hydroxypiperi- din-1-yl]methyl}pyrro-lo[2,1-f][1,2,4]triazin-4-yl)amino]benzonitrile 364 0.948 206

(3S,4R)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin- 5-yl}-methyl)piperidin-3-ol391 1.394 207

(3S,4R)-4-amino-1-({4-[(4-fluoro-3- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.092 208

(3S,4R)-4-amino-1-[(4-{[3- (difluoromethoxy)- phenyl]amino}pyrrolo[2,1-f][1,2,4]triazin- 5-yl)-methyl]piperidin-3-ol 405 1.312 209

(3S,4R)-4-amino-1-({4-[(3-ethynylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}methyl) piperidin-3-ol 3631.224 210

(3S,4R)-4-amino-1-({4-[(4-fluoro-3- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 371 1.346 211

(3S,4R)-4-amino-1-({4-[(2-fluoro-5- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl-methyl)piperidin-3-ol 387 1.182

EXAMPLES 212 TO 219

Compounds 212-219 (with HPLC note (b)) were similarly prepared fromCompound 1B, the corresponding anilines and Compound 203J, as used forCompound 146.

HPLC [M + Ret Time Ex. R Compound Name H] (min) 212

(3R,4S)-4-amino-1-({4-[(4-fluoro-3- methyl-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 371 1.298 213

(3R,4S)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}meth-yl)piperidin-3-ol 3631.218 214

(3R,4S)-4-amino-1-({4-[(3-methylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}methyl) piperidin-3-ol 3531.253 215

(3R,4S)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin- 5-yl}-methyl)piperidin-3-ol391 1.354 216

(3R,4S)-4-amino-1-({4-[(3- chlorophenyl)amino ]pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-ol 373 1.304 217

(3R,4S)-4-amino-1-({4-[(4-fluoro-3- methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidin-3-ol 387 1.086 218

3-[(5-{[(3R,4S)-4-amino-3-hydroxypipe- ridin-1-yl]methyl}pyr-ro-lo[2,1-f][1,2,4]tria-zin-4-yl)amino]benzo-nitrile 364 0.932 219

(3R,4S)-4-amino-1-[(4-{[3- (difluoromethoxy)phenyl]amino}pyrrolo[2,1-]][1,2,4]triazin- 5-yl)-methyl]piperidin-3-ol405 1.318

EXAMPLE 220(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ylcarbamate

Preparation of Compound 220A (Chiral)

To a solution of Compound 146A (121 mg, 0.5 mmol) in 1 mL of dry CH₂Cl₂cooled at 0° C., was added trichloroacetylisocyanate (0.075 mL, 0.6mmol). The reaction mixture was stirred at 0° C. for 1.0 hr. MeOH (0.5mL) was added and the reaction mixture was concentrated in vacuo to givecrude Compound 220A as a foam. ¹H-NMR (400 MHz, CDCl₃): 8.35 (bs, 1H),4.67 (bs, 1H), 3.90 (m, 1H), 3.65 (m, 2H), 3.25 (m, 2H), 2.02 (m, 1H),1.60 (m, 1H), 1.38 (s, 9H).

Preparation of Compound 220B(Chiral)

To a solution of 220A (0.5 mmol) in 3 mL of dry MeOH was added asolution of 20% aq. K₂CO₃ (2 mL) and the reaction mixture was stirred atroom temperature for 2.0 hrs. Water (15 mL) was added and the MeOH wasremoved by rotary evaporation. The mixture was extracted with EtOAc (×2)and dried over anhydrous Na₂SO₄. Concentration in vacuo afforded crude220B as an oil. ¹H-NMR (400 MHz, CDCl₃): 4.70 (bs, 2H), 4.50 (m, 1H),3.90 (bs, 1H), 3.68 (m, 1H), 3.50 (m, 1H), 3.03 (m, 1H), 1.90 (m, 1H),1.50 (m, 1H), 1.38 (s, 9H).

Preparation of Compound 220C(Chiral)

A mixture of 220B (0.5 mmol) in 5 mL of dry CH₂Cl₂ and 5 mL of TFA wasstirred at 0° C. for 1.0 hr. The mixture was concentrated in vacuo,azeotropically evaporated several times with CH₂Cl₂-MeOH-hexane anddried under high vacuum to afforded crude 220C as an oil.

Preparation of Compound 220D(Chiral)

Compound 220D was prepared from Compound 220C in a similar way asCompound 146E. It had an analytical HPLC retention time=1.793 min.(Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺=438.

Compound 220 was prepared from Compound 220D in a similar way asCompound 146. It had an analytical HPLC retention time=1.310 min.(Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺=412.

EXAMPLES 221 TO 227

Compounds 221-227 (with HPLC note (b)) were similarly prepared fromCompound 1B, corresponding anilines and Compound 220C as Compound 146.

HPLC [M + Ret Time Ex. R Compound Name H] (min) 221

(3R,4R)-4-amino-1-({4-[(5-cyano-2-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}-methyl)piperidin-3-ylcarbamate 425 1.545 222

(3R,4R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}- methyl)piperidin-3-ylcarbamate 406 1.562 223

(3R,4R)-4-amino-1-({4-[(3-methylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}- methyl)piperidin-3-ylcarbamate 396 1.381 224

(3R,4R)-4-amino-1-({4-[(4-fluoro-3-methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}methyl)piperidin-3-ylcarbamate 430 1.236 225

(3R,4R)-4-amino-1-({4-[(3-chlorophenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}methyl) piperidin-3-ylcarbamate416 1.782 226

(3R,4R)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}-methyl)piperidin-3-ylcarbamate 434 1.849 227

(3R,4R)-4-amino-1-({4-[(3-cyanophenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}methyl )piperidin-3-ylcarba-mate 407 1.486

EXAMPLE 229(3R,4S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-ylcarbamate

229A. Preparation of Compound 229A (Chiral)

Compound 229A was prepared from Compound 2031 in a similar way asCompound 135E, step 2.

229B. Preparation of Compound 229B (Chiral)

Compound 229B was prepared from Compound 229A in a similar way asCompound 220A.

229C. Preparation of Compound 229C (Chiral)

Compound 229C was prepared from Compound 229B in a similar way asCompound 220B.

229D. Preparation of Compound 229D

Compound 229D was prepared from Compound 229C in a similar way asCompound 220C.

Compound 229 was prepared from Compound 229D in a similar way asCompound 146. It had an analytical HPLC retention time=1.229 min.(Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺=412.

EXAMPLES 230 TO 236

Compounds 230 to 236 (with HPLC note (b)) were similarly prepared fromCompound 1B, corresponding anilines and Compound 229D as Compound 146.HPLC [M + Ret Time Ex. R Compound Name H] (min) 230

(3S,4R)-4-amino-1-({4-[(3- chlorophenyl)amino]pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-yl carba- mate 416 1.506 231

(3S,4R)-4-amino-1-({4-[(3-chloro-4-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}-methyl)piperidin-3-ylcarbamate 434 1.573 232

(3S,4R)-4-amino-1-({4-[(3- cyanophenyl)amino ]pyrrolo[2,1-f][1,2,4]-triazin-5-yl}methyl)-piperidin-3-yl carbamate 407 1.211 233

(3S,4R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}- methyl)piperidin-3-ylcarbamate 406 1.396 234

(3S,4R)-4-amino-1-({4-[(3-methylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}- methyl)piperidin-3-ylcarbamate 396 1.273 235

(3S,4R)-4-amino-1-({4-[(4-fluoro-3-methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}-methyl)piperidin-3-ylcarbamate 430 1.173 236

(3S,4R)-4-amino-1-({4-[(5-cyano-2-fluoro-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5- yl}-methyl)piperidin-3-ylcarbamate 425 1.230

EXAMPLE 237(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-3-methylpiperidin-3-ol(Chiral, Enantiomer A)

Preparation of Compound 237A (racemic)

To a solution of N-benzyltetrahydropyridine (100 mmol) in 150 mL ofbenzene was added solid NaHCO₃ (4.2 g, 49 mmol), followed by methylchloroformate (9.3 mL, 120 mmol) dropwise via a syringe at roomtemperature. The reaction mixture was heated to reflux for 3 hrs. Aftercooling to room temperature, the volatiles were removed by evaporationunder reduced pressure and the residue was dissolved in EtOAc (100 mL)and washed with water (20 ml×2), 0.5 M HCl (20 mL) and brine (20 mL),and dried over anhydrous MgSO₄. The reaction mixture was concentrated invacuo and the residual benzyl chloride was further removed under highvacuum (bp. 42-50° C./2 mmHg, bath temperature: 75-80° C.) to giveCompound 237A as a viscous syrup. Flash chromatography (hexane-EtOAc:9.5:0.5 to 9:1) on silica gel afforded 11.77 g (Yield: 76%) of Compound237A as an oil. ¹H-NMR (400 MHz, CDCl₃): 5.52 (bs, 1H), 3.78 (m, 2H),3.70 (s, 3H), 3.46 (m, 2H), 2.08 (m, 2H), 1.68 (s, 3H).

Preparation of Compound 237B (racemic)

The mixture of Compound 237A (775 mg, 5.0 mmol) and m-CPBA (1.21 g, 7.0mmol, 77% max) in 10 mL of dry CH₂Cl₂ was stirred overnight at roomtemperature. The precipitate was removed by filtration and the filtratewas washed by 10% Na₂S₂O₃, sat'd NaHCO₃ and brine, and dried overanhydrous MgSO₄. Concentration in vacuo afforded crude Compound 237B asan oil. ¹H-NMR (400 MHz, CDCl₃): 3.65-3.75 (m, 2H), 3.68 (s, 3H), 3.60(m, 1H), 3.33 (m, 2H), 3.12 (m, 1H), 2.07 (m, 1H), 1.92 (m, 1H), 1.35(s, 3H).

Preparation of Compound 237C (racemic)

To a solution of Compound 237B (5.0 mmol) in 10 mL of DMF was added NaN₃(810 mg, 12.4 mmol) in a 2:1 mixture of 10 mL of acetone-H₂O and themixture was heated at 80° C. overnight. After cooling to roomtemperature, EtOAc was added and the mixture was washed by water, 10%LiCl aq. solution and dried over anhydrous Na₂SO₄. Concentration invacuo afforded 1.09 g of Compound 237C as an oil. ¹H-NMR (400 MHz,CDCl₃): 3.70 (s, 3H), 3.72 (m, 1H), 3.50 (m, 2H), 3.35 (m, 1H), 3.20(bs, 1H), 2.03 (m, 1H), 1.63 (m, 1H), 1.20 (s, 3H).

Preparation of Compound 237D (racemic)

The mixture of Compound 237C (428 mg, 2.0 mmol) and 150 mg of Pd(OH)₂ in10 mL of MeOH was stirred under hydrogen atmosphere (balloon) for 4.0hrs. The catalyst was removed by filtration and the filtrate wasconcentrated in vacuo to give a crude residue.

The residue was taken into 5 mL of dry CH₂Cl₂ and to this was addedBoc₂O (460 mg, 2.10 mmol) and triethylamine (0.334 mL, 2.40 mmol). Afterstirring at room temperature overnight, the reaction mixture was dilutedwith was CH₂Cl₂ and washed with 10% citric acid, sat'd NaHCO₃ and dried(Na₂SO₄)—Concentration in vacuo followed by flash chromatography(hexane-EtOAc: 7:3 to 1:1) on silica gel gave 330 mg of 237D as an oil.¹H-NMR (400 MHz, CDCl₃): 4.78 (m, 1H), 3.90-4.40 (m, 3H), 3.70 (s, 3H),3.60 (m, 1H), 2.70-3.00 (m, 2H), 1.80 (m, 1H), 1.45 (s, 9H), 1.40 (m,1H), 1.10 (s, 3H).

Preparation of Compound 237E (racemic)

Compound 237E was prepared from Compound 237D in a similar way asCompound 146I.

Preparation of Compound 237F (racemic)

Compound 237F was prepared from Compound 237E in a similar way asCompound 1D.

Preparation of Compound 237G (racemic)

Compound 237G was prepared from Compound 237F in a similar way asCompound 1E. It had an analytical HPLC retention time=1.262 min.(Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺+1=383.

Compound 237 was obtained from 237G by chiral preparative HPLCseparation (Chiralpak AD, 250×4.6 mm, 10 micron, eluted by EtOH/MeOH/DEA50:50:0.1) as the first peak (Rt=5.390 min) with ee % ≧99%. It had ananalytical HPLC retention time=1.51 min. (Chromolith SpeedROD 4.6×50 mmcolumn, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=383.

EXAMPLE 238(3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-3-methylpiperidin-3-ol(Chiral, Enantiomer B)

Compound 238 was obtained from 237G by chiral preparative HPLCseparation (Chiralpak AD, 250×4.6 mm, 10 micron, eluted by EtOH/MeOH/DEA50:50:0.1) as the second peak (Rt=8.523 min) with ee % ≧99%. It had ananalytical HPLC retention time=1.51 min. (Chromolith SpeedROD 4.6×50 mmcolumn, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=383.

EXAMPLE 239(3R,4r,5S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol

239A. Preparation of (±)-ethyl 3-acetoxy-4-bromopiperidine-1-carboxylate

A mixture of Compound 203A/B (racemic mixture) (107 g, 371 mmol) andacetic anhydride (101 mL) in 165 mL of dry pyridine was stirred at roomtemperature for 2.0 hrs. The solvent was removed under reduced pressureand the residue was diluted with water and made basic with K₂CO₃. Themixture was extracted with chloroform (250 mL×3) and the combinedextracts were washed with water and dried over anhydrous MgSO₄.Concentration in vacuo afforded crude 239A as an oil. ¹H-NMR (400 MHz,CDCl₃): 4.90 (bs, 1H), 4.13 (q, J=7.08, 2H), 4.10 (m, 1H), 3.89 (m, 1H),3.60 (m, 1H), 3.50 (m, 2H), 2.34 (m, 1H), 2.08 (s 3H), 1.93 (m, 1H),1.27 (t, J=7.80, 3H).

239B. Preparation of (±)-ethyl5-acetoxy-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of Compound 239A (371 mmol) and DBU (92 g, 604 mmol) washeated to 90-110° C. for 30 min. After cooling to room temperature, themixture was diluted with toluene and stirred for an additional 30 min.The precipitate was removed by filtration and rinsed with toluene.Combined filtrates were washed with 1.0 N HCl, water and dried overanhydrous anhydrous MgSO₄. Concentration in vacuo afforded 67.56 g(yield: 85.4%) of 239B as an oil. ¹H-NMR (400 MHz, CDCl₃): 6.00 (bs,1H), 5.90 (bs, 1H), 5.20 (m, 1H), 4.20 (q, J=7.08, 2H), 4.19 (m, 1H),3.85 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 2.08 (s, 3H), 1.28 (t, J=7.08,3H).

239C. Preparation of (±)-ethyl5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of Compound 239B (10.5 g, 49.2 mmol) in 30 mL of EtOH wasadded a solution of 0.2N NaOH in EtOH (65 mL) and the mixture wasstirred at 0° C. for 30 min. After warming to room temperature, thereaction mixture was neutralized with glacial acetic acid. Concentrationin vacuo afforded 8.5 g of 239C as an oil. ¹H-NMR (400 MHz, CDCl₃): 5.90(m, 1H), 5.82 (bs, 1H), 4.20 (bs, 1H), 4.18 (q, J=7.08, 2H), 4.04 (m,1H), 3.85 (m, 1H), 3.55 (m, 2H), 1.28 (t, J=7.08, 3H).

239D. Preparation of (±)-ethyl5-(tert-butyldimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of Compound 239C (16 g, 93.5 mmol) in 150 mL of dry CH₂Cl₂at 0° C. was added imidazole (9.5 g, 140.0 mmol) andt-butyldimethylsilylchloride (15.5 g, 102.8 mmol) and the mixture wasstirred at ambient temperature overnight. The reaction mixture wasdiluted with ether (500 mL) and water (1 L) at 0° C. The organic phasewas separated and washed with 10% LiCl (150 mL×3), dried over anhydrousMgSO4. Concentration in vacuo followed by flash chromatography(hexane-EtOAc: 15:1 to 10:1) afforded 25.2 g (Yield: 94.4%) of 239D asan oil.

239E. Preparation of (±)-ethyl5-hydroxy-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate

To a solution of Compound 239D (25.2 g, 88.3 mmol) in 250 mL of CH₂Cl₂at 0° C. was added solid m-CPBA (39.6 g, 176.6 mmol, 77% max) in smallportions while the internal temperature was kept below 0° C. during theaddition. The mixture was stirred at 0° C. for 30 min and then roomtemperature for 4.0 hrs. More solid m-CPBA (39.6 g, 176.6 mmol, 77% max)was added in small portions and the mixture was stirred at roomtemperature for three days. The precipitate was removed by filtrationand the filtrate was washed with 20% Na₂S₂O₃ (500 mL×3), sat'd NaHCO₃(500 mL×3) and brine (250 mL), dried over anhydrous Na₂SO₄. Purificationby flash chromatography (hexane-EtOAc: 9.5:0.5 to 9:1) on silica gelafforded 4.33 g of 239E (lower Rf) as an oil.

239F. Preparation of (±)-ethyl5-(tert-butyldimethylsilyloxy)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate 239F

Compound 239F was prepared from 239D in a same reaction as Compound 239Eas an oil.

239G. Preparation of (±)-ethyl5-hydroxy-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate

To a solution of Compound 239E (4.33 g, 14.4 mmol) in 10 mL of dry THFwas added a solution of TBAF (17.2 mL, 17.2 mmol) in THF. The mixturewas stirred overnight at room temperature. Water was added and thereaction mixture was extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine and dried over Na₂SO₄.Concentration in vacuo followed by flash chromatography (hexane-EtOAc:1:1 to 1:2) on silica gel afforded 2.01 g (Yield: 74.5%) of 239G as anoil. ¹H-NMR (400 MHz, CDCl₃): 4.13 (q, J=7.08, 2H), 4.05 (m, 1H), 3.80(m, 1H), 3.70 (d, J=10.15, 1H), 3.62 (m, 1H), 3.45 (m, 2H), 3.13 (dd,J=10.15, J=7.63, 1H), 2.40 and 2.25 (partial, 1H), 1.27 (t, J=7.08, 3H).

239H. Preparation of (±)-ethyl5-hydroxy-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate

To a solution of Compound 239F (13.6 g, 45.1 mmol) in 10 mL of dry THFwas added a solution of TBAF (67.6 mL, 67.6 mmol) in THF. The mixturewas stirred overnight at room temperature. Water was added and thereaction mixture was extracted with EtOAc (250 mL×3). The combinedorganic layers were washed with brine and dried over anhydrous Na₂SO₄.Concentration in vacuo followed by flash chromatography (hexane-EtOAc:1:1 to 1:2) on silica gel afforded 6.03 g (Yield: 75%) of 239H as anoil.

¹H-NMR (400 MHz, CDCl₃): 4.15 (m, 1H), 4.13 (q, J=7.08, 2H), 3.95 (m,1H), 3.75 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.25 (m, 2H), 3.10 and2.55 (partial, 1H), 1.27 (t, J=7.08, 3H).

239I. Preparation of (±)-ethyl4-azido-3,5-dihydroxypiperidine-1-carboxylate

To a solution of Compound 239G (2.0 g, 10.7 mmol) in 2-methoxyethanol(40 mL) was added NaN₃ (3.5 g, 53.4 mmol) and NH₄Cl (2.3 g, 42.72 mmol).The reaction mixture was heated at 125° C. overnight. After cooling toroom temperature, the solvent was removed under reduced pressure and theresidue was taken into EtOAc (50 mL), washed with water (10 mL×2) anddried over anhydrous Na₂SO₄. Concentration in vacuo followed by flashchromatography (hexane-EtOAc: 1:1 to 1:2) on silica gel afforded 0.64 gof 239I (higher Rf) as a crystalline material. The stereochemistry wasconfirmed by a single x-ray crystallographic determination.

239J. Preparation of (±)-ethyl4-azido-3,5-dihydroxypiperidine-1-carboxylate

Compound 239J was prepared from 239H in a similar reaction as Compound239I as a crystalline material.

239K. Preparation of (meso)-4-azido-3,5-bis(methoxymethoxy)piperidine

To a solution of Compound 2391 (640 mg, 2.78 mmol) in dry CH₂Cl₂ (5 mL)was added i-Pr₂NEt (5.9 mL, 33.4 mmol), followed by MOMCl (1.69 mL, 22.2mmol). The reaction mixture was heated at 60° C. overnight. Aftercooling to room temperature, the reaction was diluted with CH₂Cl₂,washed with 10% citric acid, sat'd NaHCO₃ and brine, and dried overanhydrous Na₂SO₄. Concentration in vacuo gave the crude intermediate asan oil, which was used immediately in the next reaction step withoutfurther purification.

The mixture of the above prepared intermediate and KOH (1.84 g, 85%) in8 mL of EtOH and 4 mL of water was heated to reflux overnight. Aftercooling to room temperature, the solvent was removed under reducedpressure and the residue was diluted with water and extracted withCH₂Cl₂ (×2). The combined organic layers were dried over anhydrousNa₂SO₄. Concentration in vacuo afforded 662 mg of 239K as an oil. Thismaterial was used directly in the next reaction step without furtherpurification.

¹H-NMR (400 MHz, CDCl₃): 4.73 (q, J=6.82 Hz, 4H), 3.41 (s, 6H),3.20-3.40 (m 5H), 2.46 (m, 2H).

239L. Preparation of(±)-(3R,5R)-rel-4-azido-3,5-bis(methoxymethoxy)-piperidine

Compound 239L was prepared from 239J in a similar reaction as Compound239K as a crystalline material.

¹H-NMR (400 MHz, CDCl₃): 4.72 (q, J=6.82 Hz, 4H), 3.92 (m, 1H), 3.79 (m,1H), 3.49 (m, 1H), 3.42 (s, 3H), 3.41 (s, 1H), 3.25 (m, 1H), 3.03 (m,1H), 2.70 (m, 1H), 2.53 (m, 1H).

239M. Preparation of(±)-(3S,4r,5R)-rel-4-azido-1-((4-(3-methoxyphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-3,5-bis(methoxymethoxy)piperidine

Compound 239M was prepared from 239K in a same reaction as Compound 146Eas a foam. Compound 239M had an analytical HPLC retention time=2.582min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) anda LC/MS M⁺+1=502⁺.

239N. Preparation of(3S,4r,5R)-rel-4-azido-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3,5-diol

The mixture of Compound 239M (0.65 mmol) and 6N HCl (2 mL) in 3 mL ofTHF was heated at 50° C. for 2 hrs. After cooling to room temperature,the mixture was made basic with NaOH, extracted with EtOAc and driedover anhydrous Na₂SO₄. Concentration in vacuo afforded 260 mg of 239N asa solid. Compound 239N had an analytical HPLC retention time=2.063 min.(Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) anda LC/MS M⁺+1=411⁺.

The mixture of Compound 239N (260 mg, 0.633 mmol) and Ph₃P (332 mg, 1.27mmol) in THF (3 mL) and water (0.3 mL) was heated at 70° C. overnight.After cooling to room temperature, the mixture was diluted with water,acidified with 2N HCl and washed with EtOAc (2×). The aqueous layer wasbasified with 2N NaOH and extracted with EtOAc (2×). The combinedorganic layers were washed once with water and dried over anhydrousNa₂SO₄. Concentration in vacuo followed by trituration with etherafforded 180 mg of 239 as a solid. Compound 239 had an analytical HPLCretention time=1.211 min (Chromolith SpeedROD column 4.6×50 mm, 10-90%aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min,monitoring at 254 nm) and a LC/MS M⁺+1=385⁺.

EXAMPLE 240(3R/S,5R/S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol

Compound 240 was prepared from 239L in a similar way as Compound 239.

Compound 240 is a solid and had an analytical HPLC retention time=1.045min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) anda LC/MS M⁺+1=384⁺.

EXAMPLE 241A(3S,5S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol(Enantiomer A, chiral)

Compound 241A (Enantiomer A) was prepared from 240 by chiral preparativeHPLC separation (using Chiralpak AD, eluted with EtOH/DEA: 100/0.1), asthe first peak (Rt=5.827 min) with ee ≧99%.

Compound 241A is a solid and had an analytical HPLC retention time=1.044min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) anda LC/MS M⁺+1=384⁺.

EXAMPLE 241B(3R,5R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol(Enantiomer B, chiral)

Compound 241B (Enantiomer B) was obtained from 240 by chiral preparativeHPLC separation (using Chiralpak AD, eluted with EtOH/DEA: 100/0.1), asthe second peak (Rt=8.430 min) with ee ≧96%.

EXAMPLES 242 TO 246

Compounds 242 to 246 (with HPLC note (b)) were prepared from either 239Lin a similar process as Compound 239.

HPLC [M + Ret Time Ex. R Compound Name H] (min) 242

(3S,5S)-4-amino-1-({4-[(4-fluoro-3-methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidine-3,5-diol 403 0.958 (4.565^(a)) Enantiomer A 243

(3R,5R)-4-amino-1-({4-[(4-fluoro-3-methoxy-phenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methyl)piperidine-3,5-diol 403 0.958 (5.395^(a)) Enantiomer B 244

rac-(3R,5R)-4-amino-1-({4-[(3- ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl )piperidine-3,5-diol 379 1.122 racemic 245

(3R,5R)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,5-diol 3791.122 (8.496^(a)) Enantiomer A 246

(3S,5S)-4-amino-1-({4-[(3-ethynylphenyl)-amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl }methyl)piperidine-3,5-diol 3791.122 (12.704^(a)) Enantiomer B^(a)Chiral normal phase HPLC conditions: Chiralpak AD, isocratic, elutedwith EtOH-DEA: 100/0.1.

EXAMPLE 247rac-5-{[(3R,4R)-4-amino-3-methoxypiperidin-1-yl]methyl}-N-(3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

247A. Preparation of (3R,4R)-rel-tert-butyl4-azido-3-methoxypiperidine-1-carboxylate

To a stirred mixture of 146A (320 mg, 1.32 mmol) and iodomethane (0.25mL, 3.96 mmol) in 4 mL of dry THF at room temperature under nitrogen wasadded 95% NaH (40.0 mg. 1.58 mmol). This mixture was stirred at roomtemperature for 15 h and then quenched by addition of 30 mL of water.The aqueous solution was extracted with EtOAc (2×40 mL). The combinedEtOAc extracts were washed with brine (30 mL), dried (MgSO₄), filteredand concentrated in vacuo to give 310 mg (Yield: 92%) of 247A. It had ananalytical HPLC retention time=2.86 min. (Phenomenox S5 C18-HC 4.6×50 mmcolumn, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+Na=279.

247B. Preparation of5-(((3R,4R)-rel-4-azido-3-methoxypiperidin-1-yl)methyl)-N-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

To a stirred solution of 247A (310 mg, 1.21 mmol) in 2 mL of CH₂Cl₂ atroom temperature was added TFA (2.00 mL, 26.0 mmoL). This mixture wasstirred at room temperature for 15 min and concentrated in vacuo to give390 mg of (3R,4R)-rel-4-azido-3-methoxypiperidine as the TFA salt.Compound 247B was prepared from this TFA salt (52.0 mg, 0.19 mmoL) in asimilar process as described for 146E. It had an analytical HPLCretention time=1.97 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min,monitoring at 220 nm) and a LC/MS M⁺+1=409.

247C. Preparation of5-(((3R,4R)-4-amino-3-methoxypiperidin-1-yl)methyl)-N-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4-amine(racemic)

Compound 247C (racemic) was prepared from 247B in a similar process asdescribed for 146. Compound 247C was purified by passing a 1 g SCXcartridge, eluted with MeOH (16 mL), followed by the elution of 2M NH₃in MeOH (16 mL). The eluant was concentrated in vacuo and furtherpurified by prep HPLC to give 26 mg of 247C (Yield: 42%) as a solid. Ithad an analytical HPLC retention time=1.51 min. (Phenomenox S5 C18-HC4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1%TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=383.

247D. Preparation of5-(((3R,4R)-4-amino-3-methoxypiperidin-1-yl)methyl)-N-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4-amine(Enantiomer A)

Compound 247D was obtained from Compound 247C by a chiral preparativeHPLC separation (Chiralpak AD, 10 micro, 2×5 cm column, 220 nm, 20mL/min, EtOH/MeOH/DEA, 50/50/0.1). Compound 247D is a solid and hasan >99% ee with the HPLC retention time=6.5 min (Chiralpak AD, 250×4.6mm, 10 micron; EtOH/MeOH/DEA: 50/50/0.1, 0.8 mL/min, 220 nM).

247E. Preparation of5-(((3S,4S)-4-amino-3-methoxypiperidin-1-yl)methyl)-N-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4-amine(Enantiomer B)

Compound 247E was obtained from Compound 247C by a chiral preparativeHPLC separation (Chiralpak AD, 10 micro, 2×5 cm column, 220 nm, 20mL/min, EtOH/MeOH/DEA, 50/50/0.1). Compound 247E is a solid and hasan >99% ee with the HPLC retention time=8.9 min (Chiralpak AD, 250×4.6mm, 10 micron; EtOH/MeOH/DEA: 50/50/0.1, 0.8 mL/min, 220 nM).

EXAMPLE 248rac-5-{[(3R,4R)-4-amino-3-methoxypiperidin-1-yl]methyl}-N-(4-fluoro-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Compound 248 was prepared from 247A in a similar process as Compound 247and had an analytical HPLC retention time=1.18 min. (Phenomenox S5C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺+1=401.

EXAMPLE 249(4aR,8aR)-rel-6-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-2(3H)-one

249A. Preparation of (3R,4R)-rel-tert-butyl4-amino-3-hydroxypiperidine-1-carboxylate

To a stirred solution of 15A (540 mg, 2.23 mmol) in 10 mL of MeOH underN₂ was added 20% Pd(OH)₂/C (108 mg). The reaction flask was purged withH₂ several times and stirred under hydrogen atmosphere for 18 hrs. Thecatalyst was removed by filtration through a 4 μM polycarbonate film andrinsed with MeOH (6×30 mL). The filtrate was concentrated in vacuo togive 453 mg (Yield: 94%) of 249A. It had an analytical HPLC retentiontime=0.73 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at220 nm) and a LC/MS M⁺+1=217.

249B. Preparation (3R,4R)-rel-tert-butyl4-(2-chloroacetamido)-3-hydroxypiperidine-1-carboxylate

To a stirred mixture of 249A (428 mg, 1.98 mmol) and NaOAc (325 mg, 3.96mmol) in 2.5 mL of acetone and 0.8 mL of water under N₂ at 0° C. wasadded dropwise chloroacetyl chloride (0.17 mL, 2.08 mmol) over 5 min.This mixture was stirred at 0° C. for 10 min and at room temperature for25 min. The mixture was diluted with 160 mL of EtOAc and washed withwater (2×40 mL), saturated NaHCO₃ solution (1×30 mL) and brine (1×30mL). The EtOAc layer was dried (MgSO₄), filtered and concentrated invacuo to give 415 mg (yield: 72%) of 249B. It had an analytical HPLCretention time=1.96 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueousmethanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min,monitoring at 220 nm) and a flow injection MS M⁻=291.

249C. Preparation (4aR,8aR)-rel-tert-butyl2-oxo-hexahydro-1H-pyrido[3,4-b][1,4]oxazine-6(7H)-carboxylate

To a stirred mixture of 249B (410 mg, 14.0 mmol) in 10 mL of dry THFunder N₂ at room temperature was added 60% NaH (84.0 mg, 2.10 mmol).This mixture was stirred at room temperature for 45 min and quenchedwith 3 mL of saturated NH₄Cl solution. The mixture was concentrated invacuo and diluted with 40 mL of saturated NaHCO₃ solution. The aqueoussolution was extracted with EtOAc (3×60 mL). The combined EtOAc extractswere washed with brine (1×30 mL). The EtOAc layer was dried (MgSO₄),filtered and concentrated in vacuo to give 344 mg (yield: 96%) of 249C.It had an analytical HPLC retention time=2.01 min. (Chromolith SpeedROD4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺=257.

249D. Preparation(4aR,8aR)-rel-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-2(3H)-one

To a stirred mixture of 249C (70.0 mg, 0.0.27 mmol) in 1 mL of CH₂Cl₂ atroom temperature was added TFA (2.00 mL, 25.9 mmol). The mixture wasstirred at room temperature for 1 hr and concentrated in vacuo to givecrude 249D. This material was mixed with DMA to make a 2 mL stocksolution and was used as is in next step reaction.

Compound 249 was prepared from 249D in a similar process as Compound146. It had an analytical HPLC retention time=1.85 min. (Phenomenox S5C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺+1=409.

EXAMPLE 2505-(((4aR,8aR)-rel-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)methyl)-N-(3-methoxyphenyl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

To a stirred mixture of Compound 249 (100 mg, 0.24 mmoL) at roomtemperature in 4 mL of dry THF was added dropwise 1M LiAlH₄/ethersolution (0.70 mL, 0.70 mmoL). This mixture was stirred at roomtemperature for 70 min and quenched by the addition of 200 mg of Celiteand 200 mg of sodium sulfate decahydrate. The mixture was stirred atroom temperature for 50 min. The insoluble was filtered off and rinsedwith MeOH (3×15 mL). The filtrate was concentrated in vacuo and purifiedby a prep HPLC to give 78 mg (yield: 81%) of Compound 250. It had ananalytical HPLC retention time=1.68 min. (Phenomenox S5 C18-HC 4.6×50 mmcolumn, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=395.

EXAMPLE 251N-(4-fluoro-3-methoxyphenyl)-5-(((4aR,8aR)-rel-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)methyl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

Compound 251 was prepared from 249D in a similar process as Compound250. It had an analytical HPLC retention time=1.64 min. (Phenomenox S5C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutescontaining 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺+1=413.

EXAMPLE 252(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-(methylsulfonyl)piperidine-3-carboxamide

252A. Preparation of 1-tert-butyl 3-ethyl4-oxopiperidine-1,3-dicarboxylate

A solution of ethyl 4-oxopiperidine-3-carboxylate (16.2 g, 95 mmol) inCHCl₃ (160 mL) was treated with a solution of NaHCO₃ (9.6 g, 114 mmol)in water (170 mL). This biphasic reaction was treated with a solution ofBoc₂O (20.7 g, 95 mmol) in CHCl₃ (60 mL). The resulting reaction washeated to reflux for 18 hours, cooled to room temperature and the layerswere separated. The aqueous layer was extracted with CHCl₃ (2×100 mL).The combined organic layers were dried (Na₂SO₄), filtered andconcentrated to give 22 g (yield: 86%) of Compound 252A as an oil.

252B. Preparation of (R)-1-tert-butyl 3-ethyl4-(1-phenylethylamino)-5,6-dihydro-pyridine-1,3(2H)-dicarboxylate

A solution of 252A (22 g, 81 mmol) and toluene (400 mL) was treated with(R)-1-phenylethanamine (12.5 mL, 97 mmol) and p-TsOH (1.5 g). Thereaction mixture was heated to reflux with a Dean-Stark trap for 23hours. The mixture was cooled to room temperature, washed with saturatedaqueos NaHCO₃ (2×200 mL) and brine (2×200 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated. The crudematerial was filtered through a pad of silica (100% CH₂Cl₂) andconcentrated to provide 14.7 g (yield: 49%) of Compound 252B as an oil.

252C. Preparation of (3S,4R)-1-tert-butyl 3-ethyl4-((R)-1-phenylethylamino)-piperidine-1,3-dicarboxylate

A 1 L 3-neck round bottom flask equipped with a mechanical stirrer andaddition funnel was charged with 252B (14.7 g, 39 mmol) and acetonitrile(200 mL) and acetic acid (100 mL). The solution was cooled to 0° C. andNa(OAc)₃BH (33.3 g, 157 mmol) was added in three portions over 2 hours.The reaction was stirred for two hours at this temperature after thefinal addition. The mixture was then cooled to −10° C. and slowlyquenched by addition of 1 N NaOH (100 mL), 4 N NaOH (100 mL), 6 N NaOH(100 mL) followed by 50% NaOH (50 mL). The reaction was warmed to roomtemperature and the layers were separated. The aqueous layer wasextracted with CH₂Cl₂ (2×250 mL) and the combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. Purification byflash chromatography (10% to 30% EtOAc/hexane gradient) on silica gelafforded 6.0 g (yield: 41%) of Compound 252C.

252D. Preparation of (3R,4R)-1-tert-butyl 3-ethyl4-((R)-1-phenylethylamino)-piperidine-1,3-dicarboxylate

A solution of 252C (2.90 g, 7.71 mmol) in ethanol (70 mL) was treatedwith 21% NaOEt in ethanol (7.5 mL). The reaction mixture was heated to50° C. for three hours, cooled to room temperature, and thenconcentrated. The resulting oil was taken up in dichloromethane (150mL), washed with 20% NH₄Cl (2×50 mL). The organic layer was dried(Na₂SO₄) and concentrated to an oil. Purification by flashchromatography (10 to 25% EtOAc/Hexane gradient) on silica gel afforded1.20 g (yield: 41%) of Compound 252D as an oil.

252E. Preparation of (3R,4R)-1-tert-butyl 3-ethyl4-aminopiperidine-1,3-dicarboxylate

A solution of 252D (1.18 g, 3.13 mmol) in MeOH (31 mL) was treated withammonium formate (1.58 g, 25.1 mmol) and 10% Pd/C. The reaction mixturewas heated to reflux for 14 hours then cooled to room temperature. Theresulting solid was removed by filtration and washed with MeOH. Thefiltrate was dried (Na₂SO₄) and concentrated under reduced pressure togive 0.82 g (yield: 96%) of Compound 252E as an oil.

252F. Preparation of (3R,4R)-1-tert-butyl 3-ethyl4-aminopiperidine-1,3-dicarboxylate

A solution of 252E (0.80 g, 2.94 mmol) in dichloromethane (29 mL) at 0°C. was treated with diisopropylethylamine (0.41 g, 3.23 mmol). Asolution of allylchloroformate (0.46 g, 3.83 mmol) in dichloromethane(29 mL) was slowly added over 30 minutes. The reaction mixture wasstirred at 0° C. for 16 hours, then slowly warmed to room temperature.The resulting solution was diluted with dichloromethane and washed withsaturated NaHCO₃ (2×50 mL). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting oil was purified byflash chromatography (20 to 25% EtOAc/Hexane) on silica gel to give 0.88g (yield: 84%) of Compound 252F as an oil.

252G. Preparation of (3R,4R)-methyl4-(allyloxycarbonyl)piperidine-3-carboxylate

A solution of 252F (0.87 g, 2.44 mmol) in dichloromethane (12 mL) wastreated with TFA (2.4 mL) at 0° C. The reaction mixture was stirred at0° C. for one hour then allowed to slowly warm to room temperature.Stirring was continued at this temperature for five hours, concentrated,and azeotropically evaporated with MeOH and toluene. The resulting oilwas purified by flash chromatography (0 to 2% MeOH/CH₂Cl₂) on silica gelto give 0.47 g (yield: 79%) of Compound 252G as an oil.

252H. Preparation of (3R,4R)-methyl4-(allyloxycarbonyl)-1-((4-(3-methoxyphenyl-amino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylate

A suspension of 252G (0.21 g, 0.87 mmol),4-(3-methoxyphenylamino)-pyrrolo[1,2,4]trizin-5-ylmethyltriethylammonium bromide (0.40 g, 0.87 mmol), and diisopropylethylamine(0.11 g, 0.87 mmol) in MeCN (15 mL) was heated to 60° C. for one hourthen concentrated in vacuo. The resulting oil was purified by fishchromatography (2 to 5% MeOH/CH₂Cl₂) on silic gel to give 0.33 g (yield:77%) of Compound 252H as a solid.

2521. Preparation of(3R,4R)-4-(allyloxycarbonyl)-1-((4-(3-methoxyphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylicacid

A solution of 252H (0.33 g, 0.67 mmol) in MeOH/THF/water (3/3/1/ mL) wastreated with LiOH monohydrate (0.25 g, 6.7 mmol). The reaction mixturewas stirred for 14 hours, neutralized to pH=7 with saturated aqueousNaHCO₃, then concentrated to a volume of 1 mL. The resulting slurry wasdissolved in MeOH and purified by preparative HPLC (YMC ODS-A 5 um,20×100 mm, solvent A 10% MeOH-90% H₂O-0.1% TFA, solvent B 90% MeOH-10%H₂O-0.1% TFA, gradient 0-100% B, 12 mintues). The desired fractions werecombined and concentrated under reduced pressure to remove most of theMeOH, neutralized with saturated aqueous NaHCO₃ to pH=7, and extractedwith EtOAc (2×50 mL). The combined organic layers were dried (Na₂SO₄)and concentrated to give 0.30 g (yield: 94%) of Compound 252I as asolid.

252J. Preparation of allyl(3R,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]-triazin-5-yl)methyl)-3-(methylsulfonylcarbamoyl)piperidin-4-ylcarbamate

A solution of 252I (0.30 g, 0.63 mmol) in MeCN (6.2 mL) was treated withdimethylaminopiperidine (77 mg, 0.63 mmol), DECI (0.18 g, 0.94 mmol),followed by methanesulfonamide (0.18 g, 1.88 mmol). The reaction mixturewas stirred for two hours, quenched with water, and concentrated. Theresulting slurry was dissolved in MeOH and purified by preparative HPLC(YMC ODS-A 5 um, 20×100 mm, solvent A 10% MeOH-90% H₂O-0.1% TFA, solventB 90% MeOH-10% H₂O-0.1% TFA, gradient 0-100% B, 12 minutes). The desiredfractions were combined and concentrated in vacuo, neutralized withsaturated aqueous NaHCO₃ to pH=10, and extracted with EtOAc (2×50 mL).The combined organic layers were dried (Na₂SO₄) and concentrated to give0.22 g (yield: 62%) of Compound 252J as a-solid.

A solution of 252J (100 mg, 0.18 mmol) in THF (4 mL, degassed withargon) was treated with Pd(PPh₃)₄ (21 mg, 0.018 mmol) and Et₂NH (33 mg,0.45 mmol). The reaction mixture was stirred for 90 minutes thenconcentrated. The resulting solid was dissolved in MeOH, purified bypreparative HPLC (YMC ODS-A 5 um, 20×100 mm, solvent A 10% MeOH-90%H₂O-0.1% TFA, solvent B 90% MeOH-10% H₂O-0.1% TFA, gradient 0-100% B, 12minutes). The desired fractions were concentrated to, neutralized withsaturated aqueous NaHCO₃ to pH=10, and extracted with EtOAc (2×50 mL).The combined organic layers were dried (Na₂SO₄) and concentrated to give36 mg (yield: 42%) of Compound 252 as a solid. It had an analytic HPLCretention time=1.62 min (Phenomenex Su C18 4.6×50 mm column 10-90%aqueous methanol containing 0.2% H₃PO₄, 4 min grad. monitored at 220nm), [M+H]⁺=474.

EXAMPLE 253(3R,4R)-4-amino-1-({4-[(3-ethynylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-methylpiperidine-3-carboxamide

253A. Preparation of (3R,4R)-methyl4-(allyloxycarbonyl)-1-((4-(3-ethynylphenyl-amino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylate

A suspension of 252G (0.24 g, 1.0 mmol),4-(3-ethylnylphenylamino)-pyrrolo[1,2,4]trizin-5-ylmethyltriethylammonium bromide (0.43 g, 1.0 mmol), and diisopropylethyl amine(0.13 g, 1.0 mmol) in MeCN (15 mL) was heated to 60° C. for one hour,then concentrated in vacuo. The residue was purified by flashchromatography (2 to 5% MeOH/CH₂Cl₂) on silica gel gave 0.24 g (yield:50%) of Compound 253A as a solid.

253B. Preparation of(3R,4R)-4-(allyloxycarbonyl)-1-((4-(3-ethynylphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylicacid

A solution of 253A (0.24 g, 0.50 mmol) in MeOH/THF/water (313111 mL) wastreated with LiOH monohydrate (0.21 g, 5.0 mmol) at room temperature.The reaction mixture was stirred for 14 hours, neutralized to pH=7 withsaturated aqueous NaHCO₃, then concentrated. The resulting slurry wasdissolved in MeOH and purified by preparative HPLC (YMC ODS-A 5 um,20×100 mm, solvent A 10% MeOH-90% H₂O-0.1% TFA, solvent B 90% MeOH-10%H₂O-0.1% TFA, gradient 0-100% B, 12 minutes). The desired fractions wereconcentrated, neutralized with saturated NaHCO₃ to pH=7, and extractedwith EtOAc (2×50 mL). The combined organic layers were dried (Na₂SO₄)and concentrated in vacuo to give 0.22 g (yield: 93%) of Compound 253Bas a solid.

253C. Preparation of allyl(3R,4R)-1-((4-(3-ethynylphenylamino)pyrrolo[1,2-f][1,2,4]-triazin-5-yl)methyl)-3-(methylcarbamoyl)piperidin-4-ylcarbamate

A solution of 253B (0.22 g, 0.46 mmol) in MeCN (4.6 mL) was treated withdiisopropylethylamine (59 mg, 0.46 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(hereinafter referred to as the “Bop Reagent”) (0.36 g, 0.69 mmol), and2 N methylamine in THF (0.70 mL, 1.38 mmol). The reaction mixture wasstirred for two hours, quenched with water, and concentrated. Theresulting slurry was dissolved in MeOH and purified by preparative HPLC(YMC ODS-A 5 um, 20×100 mm, solvent A 10% MeOH-90% H₂O-0.1% TFA, solventB 90% MeOH-10% H₂O-0.1% TFA, gradient 0-100% B, 12 minutes). The desiredfractions were concentrated, neutralized by saturated aqueous NaHCO₃ topH=10, and extracted with EtOAc (2×50 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated in vacuo to give 0.21 g (yield:92%) of Compound 253C as a solid.

A solution of 253C (100 mg, 0.20 mmol) in THF (5 mL, degassed withargon) was treated with Pd(PPh₃)₄ (23 mg, 0.020 mmol) and Et₂NH (37 mg,0.51 mmol). The reaction mixture was stirred for 90 minutes, and thenconcentrated. The resulting solid was dissolved in MeOH and purified bypreparative HPLC (YMC ODS-A 5 um, 20×100 mm, solvent A 10% MeOH-90%H₂O-0.1% TFA, solvent B 90% MeOH-10% H₂O-0.1% TFA, gradient 0-100% B, 12minutes). The desired fractions were concentrated, neutralized withsaturated aqueous NaHCO₃ to pH=10, and extracted with EtOAc (2×50 mL).The combined organic layers were dried (Na₂SO₄) and concentrated invacuo to give 36 mg (yield: 42%) of Compound 253 as a solid. It had ananalytic HPLC retention time=1.96 min (Phenomenex Su C18 4.6×50 mmcolumn 10-90% aqueous methanol containing 0.2% H₃PO₄, 4 min grad.monitored at 220 nm), [M+H]⁺=404.

EXAMPLE 254(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-methylpiperidine-3-carboxamide

254A. Preparation of (3R,4R)-1-tert-butyl 3-ethyl4-(benzyloxycarbonyl)piperidine-1,3-dicarboxylate

A solution of 252E (180 mg, 0.66 mmol) in CH₂Cl₂ (5 mL) was treated withbenzyloxychloroformate (0.1 mL, 0.73 mmol) and triethylamine (0.12 mL,0.86 mmol). The reaction was stirred at room temperature for 18 hours,diluted with CH₂Cl₂ (10 mL) and washed with water (2×10 mL), 0.1 N HCl(2×10 mL), saturated aqueous NaHCO₃ (2×10 mL) and brine (1×10 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated to give 243mg (yield: 91%) of Compound 254A as an oil.

254B. Preparation of (3R,4R)-ethyl4-(benzyloxycarbonyl)piperidine-3-carboxylate

A solution of 254A (243 mg, 0.60 mmol) in CH₂Cl₂ (3 mL) at 0° C. wastreated with trifluoroacetic acid (0.3 mL). The reaction was stirred atroom temperature for one hour, then concentrated to an oil. The crudeamine was dissolved in EtOAc (10 mL), washed with saturated aqueousNaHCO₃ and dried (Na₂SO₄), filtered and concentrated in vacuo. Theproduct was purified by flash chromatography (10% MeOH/CH₂Cl₂) on silicagel to afford 95 mg (yield: 52%) of Compound 254B.

254C. Preparation of (3R,4R)-methyl4-(benzyloxycarbonyl)-1-((4-(3-methoxyphenyl-amino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylate

A suspension ofN,N-diethyl-N-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)ethanaminiumbromide (1.7 g, 3.62 mmol) and 254B (1.06 g, 3.6 mmol) in acetonitrile(75 mL) was treated with DIEA (0.63 mL, 3.6 mmol) and warmed to 55° C.for 12 hours. The reaction was concentrated, dissolved in EtOAc (100 mL)and washed with water (2×100 mL). The crude material was dried (Na₂SO₄),filtered and concentrated to afford 1.7 g (yield: 89%) of Compound 254C.

254D. Preparation of(3R,4R)-4-(benzyloxycarbonyl)-1-((4-(3-methoxyphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylicacid

Compound 254D (1.67 g, yield: 100%) was prepared from 254C (1.7 g, 3.13mmol) in a similar process as used for Compound 252I.

254E. Preparation of Benzyl(3R,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-3-(methylcarbamoyl)piperidin-4-ylcarbamate

Compound 254E (790 mg, yield: 54%) was prepared from 254D (1.44 g, 2.71mmol) in a similar process as used for Compound 253C.

A solution of 254E (1.66 g, 3.13 mmol) in MeOH (50 mL) was purged withargon for 30 minutes. 5% Pd/C (300 mg) was added. The reacton mixturewas stirred under a hydrogen atmosphere for three hours, then filteredthrough a pad of celite. The filtrate was concentrated in vitro toprovide 1.21 g (yield: 94%) of Compound 254 as a solid. It had ananalytical HPLC retention time=1.57 min (YMC S5 ODS 4.6×50 mm, 10-90%aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220nm), [M+H]⁺=410.

EXAMPLE 255(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3-carboxylicacid

Compound 255 (33 mg, yield: 89%) was prepared from 254D (50 mg, 0.094mmol) in a similar process as used for 254. It had an analytical HPLCretention time=1.54 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanolcontaining 0.2% H₃PO₄, 4 min gradient, monitored at 220 nm). [M+H]⁺=397.

EXAMPLE 256(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3-carboxamide

256A. Preparation of Benzyl(3R,4R)-3-((3,4-dimethoxybenzyl)carbamoyl)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidin-4-ylcarbamate

A solution of 254D (150 mg, 0.23 mmol) in DMF (5 mL) was treated with3,4-dimethoxybenzylamine (77 mg, 0.46 mmol), DIEA (80 μL, 0.46 mmol) andBop Reagent (132 mg, 0.25 mmol). The reaction was stirred at roomtemperature for four hours, then poured into EtOAc (25 mL). The mixturewas washed with saturated aqueous NaHCO₃ (3×25 mL) and dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified byflash chromatography (3% MeOH/CH₂Cl₂) on silica gel to afford 174 mg(yield: 95%) of Compound 256A.

A solution of 256A (50 mg, 0.06 mmol) in TFA (3 mL) was stirred at roomtemperature for 5 days. The reaction was concentrated and purified bypreparative HPLC to afford 7 mg (yield: 30%) of Compound 256 as a solid.It had an analytical HPLC retention time=1.62 min (YMC S5 ODS 4.6×50 mm,10-90% aqueous methanol containing 0.2% H₃PO₄, 4 min gradient, monitoredat 220 nm), [M+H]⁺=396.

EXAMPLE 257(3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-(methylsulfonyl)piperidine-3-carboxamide

257A. Preparation of (3S,4R)-1-tert-butyl 3-methyl4-aminopiperidine-1,3-dicarboxylate

Compound 257A (447 mg, 63%) was prepared in a similar process as usedfor 252E.

257B. Preparation of (3S,4R)-1-tert-butyl 3-methyl4-(benzyloxycarbonyl)piperidine-1,3-dicarboxylate

A solution of 257A (447 mg, 1.7 mmol) in CH₂Cl₂ (20 mL) was treated withtriethylamine (0.3 mL, 2.2 mmol) followed by benzyl chloroformate (0.27mL, 1.9 mmol) at room temperature. The reaction mixture was stirred for18 hours, then washed with water (25 mL). The aqueous layer wasextracted with CH₂Cl₂ (25 mL) and the combine organics were washed withsaturated aqueous NaHCO₃, 0.1N HCl, and brine. The organic layer wasdried (Na₂SO₄), filtered and concentrated in vacuo to an oil. The crudematerial was purified by flash chromatography (30% EtOAc/hexanes) onsilica gel to afford 411 mg (yield: 75%) of Compound 257B as an oil.

257C. Preparation of (3S,4R)-methyl4-(benzyloxycarbonyl)piperidine-3-carboxylate

A solution of 257B (411 mg, 1.04 mmol) in CH₂Cl₂ (5 mL) was treated withTFA (0.5 mL) at room temperature. The reaction mixture was stirred for5.0 hours, then concentrated in vacuo. The residue was dissolved inEtOAc (10 mL) and washed with saturated aqueous NaHCO₃. The organicswere dried (Na₂SO₄), filtered and concentrated in vacuo to give 365 mgof 257C as a solid.

257D. Preparation of (3S,4R)-methyl4-(benzyloxycarbonyl)-1-((4-(3-methoxyphenyl-amino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylate

A suspension of 257C (292 mg, 0.62 mmol) andN,N-diethyl-N-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)ethanaminiumbromide (292 mg, 0.62 mmol) in acetonitrle (10 mL) were treated withDIEA (0.2 mL, 1.24 mmol) at room temperature. The reaction mixture waswarmed to 55° C. for 3.0 hours, then concentrated in vacuo to dryness.The crude residue was purified by flash chromatography (30%EtOAc/hexanes) on silica gel to afford 269 mg (yield: 80%) of 257D.

257E. Preparation of(3S,4R)-4-(benzyloxycarbonyl)-1-((4-(3-methoxyphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylicacid

A solution of 257D (200 mg, 0.37 mmol) in THF/MeOH (1:1, 4 mL) wastreated with LiOH monohydrate (30 mg, 0.74 mmol) in water (1 mL) at roomtemperature. The reaction mixture was stirred for eight hours, thenconcentrated to 1 mL. The residue was diluted with water (10 mL) andextracted with EtOAc (3×10 mL). The organics were dried (Na₂SO₄),filtered and concentrated in vacuo to afford 200 mg (yield: 100%) ofCompound 257E as a solid.

257F. Preparation of(3S,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-3-(methylsulfonylcarbamoyl)piperidin-4-ylcarbamateacid

A solution of 257E (30 mg, 0.06 mmol) in DMF (2 mL) was treated withmethansulfonamide (11 mg, 0.11 mmol), DMAP (7 mg, 0.06 mmol) and EDAC(13 mg, 0.07 mmol). The reaction mixture was stirred at room temperaturefor 48 hours. The resulting suspension was diluted with EtOAc (10 mL),washed with brine (3×10 mL), saturated aqueous NaHCO₃ (2×10 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to afford 35 mg of 257Ewhich was used without further purification.

A solution of 257F (35 mg) in MeOH (3 mL) was treated with 10% Pd/C (15mg) and stirred under a hydrogen atmosphere for three hours at roomtemperature. The slurry was filtered through a nylon filter and thefiltrate was concentrated. The crude material was purified bypreparative HPLC to afford 12 mg of Compound 257 as a solid. It had ananalytical HPLC retention time=1.77 min (YMC S5 ODS 4.6×50 mm, 10-90%aqueous methanol containing 0.2% H₃PO₄, 4 min gradient, monitored at 220nm) [M+H]⁺=474.

EXAMPLE 258(3R,4S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-(methylsulfonyl)piperidine-3-carboxamide

258A. Preparation of (3R,4S)-1-tert-butyl 3-methyl4-((S)-1-phenylethylamino)-piperidine-1,3-dicarboxylate

Compound 258A was prepared in the same manner as 252C using theappropriate starting materials.

258B. Preparation of (3R,4S)-1-tert-butyl 3-methyl4-aminopiperidine-1,3-dicarboxylate

Compound 258B was prepared according to the procedures described inExample 257 using the appropriate starting materials.

Compound 258 was prepared from 258B in the same manner as described for257. Compound 258 had an analytical HPLC retention time=1.77 min (YMC S5ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H₃PO₄, 4 mingradient, monitored at 220 nm) [M+H]⁺=474.

EXAMPLE 259(3S,4R)-4-amino-1-({4-[(3-ethynylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)-N-methylpiperidine-3-carboxamide

259A. Preparation of (3S,4R)-1-tert-butyl 3-ethyl4-aminopiperidine-1,3-dicarboxylate

A solution of 252C (2.6 g, 6.9 mmol) in EtOH (100 mL) was treated withammonium formate (3.5 g, 55.3 mmol) and 10% Pd/C (390 mg). The reactionmixture was heated to reflux under a nitrogen atmosphere for threehours. The resulting suspension was filtered through a pad of celite andconcentrated in vacuo to afford 1.8 g (yield: 96%) Compound 259A as asolid.

259B. Preparation of ((3S,4R)-1-tert-butyl 3-ethyl4-(allyloxycarbonyl)piperidine-1,3-dicarboxylate

A solution of 259A (900 mg, 3.3 mmol) in CH₂Cl₂ (20 mL) was treated withtriethylamine (0.64 mL, 4.62 mmol) and allylchloroformate (0.35 mL, 3.96mmol) at room temperature. The mixture was stirred for four hours, thenwashed with 0.1 N HCl (2×10 mL), 1N NaOH (2×10 mL) and brine (10 mL).The organic layer was dried (Na₂SO₄), filtered and concentrated in vacuoto give 680 mg (yield: 58%) of Compound 259B as an oil.

259C. Preparation of (3S,4R)-ethyl4-(allyloxycarbonyl)piperidine-3-carboxylate

A solution of 259B (680 mg, 1.9 mmol) in CH₂Cl₂ (10 mL) was treated withTFA (1 mL) at room temperature. The reaction mixture was stirred for 16hours, then concentrated. The residues was dissolved in EtOAc (20 mL)and washed with saturated aqueous NaHCO₃ (2×20 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to afford 170 mg of Compound 259C.

259D. Preparation of (3S,4R)-methyl4-(allyloxycarbonyl)-1-((4-(3-ethynylphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylate

A suspension of 259C (50 mg, 0.2 mmol) andN,N-diethyl-N-((4-(3-ethynylphenyl-amino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)ethanaminiumbromide (82 mg, 0.18 mmol) in acetonitrile (2 mL) were treated with DIEA(31 μL, 0.18 mmol). The mixture was heated to 65° C. for 6.0 hours,cooled to room temperature and concentrated. The crude material waspurified by radial chromatography (SiO₂, 2 mm plate, 100% CH₂Cl₂ to 1%MeOH/CH₂Cl₂ gradient) to afford 63 mg (yield: 70%) of Compound 259D.

259E. Preparation of(3S,4R)-4-(allyloxycarbonyl)-1-((4-(3-ethynylphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylicacid

A solution of 259D (63 mg, 0.13 mmol) in THF/MeOH (1:1, 4 mL) wastreated with a solution of LiOH monohydrate (17 mg, 0.39 mmol) at roomtemperature. The reaction mixture was stirred for 18 hours, thenconcentrated to 0.5 mL volume. The residues was diluted with water (5mL) and brought to pH 6 with saturated aqueous NH₄Cl solution. Themixture was extracted with EtOAc (2×10 mL), the organic layers weredried (Na₂SO₄) filtered and concentrated in vacuo to afford 56 mg(yield: 92%) of Compound 259E.

259F. Preparation of allyl(3S,4R)-1-((4-(3-ethynylphenylamino)pyrrolo[1,2-f][1,2,4]-triazin-5-yl)methyl)-3-(methylcarbamoyl)piperidin-4-ylcarbamate

A solution of 259E (56 mg, 0.12 mmol) in DMF (3 mL) was treatedsequentially with methylamine (2M in THF, 0.12 mL, 0.24 mmol), DIEA(0.02 mL, 0.12 mmol) and Bop Reagent (68 mg, 0.13 mmol). The reactionmixture was stirred for 18 hours at room temperature. The resultingmixture was diluted with EtOAc (25 mL), washed with brine (3×15 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The crude 259E (71mg) was used without further purification.

A solution of 259F (71 mg, 0.15 mmol) in THF(3 mL) was degassed withargon and treated with diethylamine (28 mg, 0.38 mmol) and Pd(PPh₃)₄ (17mg, 0.02 mmol). The reaction was stirred under an argon atmosphere for2.0 hours, then concentrated in vacuo and purified by preparative HPLCto afford 14 mg of Compound 259. It had an analytical HPLC retentiontime=2.10 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing0.2% H₃PO₄, 4 min gradient, monitored at 220 nm) [M+H]⁺=404.

EXAMPLE 260(3S,4S)-4-amino-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-N-methylpiperidine-3-carboxamide

260A. Preparation of (3S,4S)-1-tert-butyl 3-methyl4-((S)-1-phenylethylamino)-piperidine-1,3-dicarboxylate

A solution of 258A (4.50 g, 12.4 mmol) in methanol (124 mL) at roomtemperature was treated with 25% NaOMe in methanol (8.04 mL). Thisreaction mixture was heated to 50° C. for 3.0 hours, cooled to roomtemperature, and then concentrated in vacuo. The oily residue wasdissolved in dichloromethane (200 mL), and washed with 20% NH₄Cl (2×75mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash chromatography (10 to 25%EtOAc/hexanes) on silica gel to give 1.50 g (yield: 30%) of Compound260A as an oil.

260B. Preparation of (3S,4S)-1-tert-butyl 3-methyl4-aminopiperidine-1,3-dicarboxylate

A solution of 260A (1.10 g, 3.03 mmol) in MeOH (31 mL) at roomtemperature was treated with ammonium formate (1.51 g, 24.3 mmol) and10% Pd/C (110 mg). The reaction mixture was heated to reflux for 14hours then cooled to room temperature. The solid material was removed byfiltration and washed with MeOH. The filtrate was concentrated in vacuoto give 0.75 g (yield: 96%) of Compound 260B as an oil.

260C. Preparation of (3S,4S)-1-tert-butyl 3-methyl4-(benzyloxycarbonyl)piperidine-1,3-dicarboxylate

A solution of 260B (0.75 g, 2.90 mmol) in dichloromethane (30 mL) at 0°C. was treated with triethylamine (0.35 g, 3.48 mmol) andN-(benzyloxycarbonyoxy)succinimide (0.72 g, 2.90 mmol). The reactionmixture was allowed to warm to room temperature and was stirred for 16hours. The reaction mixture was diluted with dichloromethane, washedwith 10% citric acid (2×50 mL), then saturated NaHCO₃ (2×50 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to give1.01 g (yield: 89%) of Compound 260C as an oil. It was used in the nextstep without further purification.

260D. Preparation of (3S,4S)-methyl4-(benzyloxycarbonyl)piperidine-3-carboxylate

A solution of 260C (1.01 g, 2.58 mmol) in dichloromethane (50 mL) at 0°C. was treated with TFA (5 mL). The reaction mixture was stirred at 0°C. for 1.0 hour then allowed to slowly warm to room temperature andstirred for an additional 2.0 hours. The mixture was concentrated, andthen azeotropically evaporated with MeOH and toluene. The residue wasdissolved in dichloromethane and washed with saturated NaHCO₃ (2×50 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo togive 0.61 g (yield: 81%) of Compound 260D as an oil. It was used in thenext step without further purification.

260E. Preparation of (3S,4S)-methyl4-(benzyloxycarbonyl)-1-((4-(3-methoxyphenyl-amino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylate

A reaction mixture of 260D (0.18 g, 0.61 mmol),4-(3-methoxyphenylamino)-pyrrolo[1,2,4]trizin-5-ylmethyltriethylammonium bromide (0.29 g, 0.61 mmol), and diisopropylethyl amine(79 mg, 0.61 mmol) in MeCN (6 mL) was heated to 55° C. for 12 hours andconcentrated in vacuo. The residue was dissolved in dichloromethane andwashed with water (2×50 mL). The dichloromethane portion was dried overNa₂SO₄ and concentrated in vacuo to give 0.33 g (yield: 99%) of Compound260E as an oil. It was used in the next step without furtherpurification. (M+H)⁺=545

260F. Preparation of(3S,4S)-4-(benzyloxycarbonyl)-1-((4-(3-methoxyphenylamino)-pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidine-3-carboxylicacid

A solution of 260E (95 mg, 0.18 mmol) in MeOH/THF/water (1/1/0.5 mL) atroom temperature was treated with LiOH monohydrate (75 mg, 1.8 mmol).The reaction mixture was stirred for 18 hours, quenched with saturatedNH₄Cl (5 mL), and extracted with EtOAc (3×15 mL). The EtOAc layer wasdried over Na₂SO₄ and concentrated in vacuo to give 80 mg (yield: 89%)of Compound 260F as a film. It was used in the next step without furtherpurification. Mass (M+H)⁺=531

260G. Preparation of benzyl(3S,4S)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-3-(methylcarbamoyl)piperidin-4-ylcarbamate

A solution of 260F (40 mg, 0.075 mmol) in DMF (0.8 mL) at roomtemperature was treated with diisopropylethylamine (10 mg, 0.075 mmol),Bop Reagent (59 mg, 0.11 mmol), then 2N methylamine in THF (0.12 mL,0.23 mmol). The reaction mixture was stirred for 16 hours, quenched withwater, and concentrated. The resulting suspension was dissolved in MeOH,and purified by preparative HPLC (YMC ODS-A 5 um, 20×100 mm, solvent A10% MeOH-90% H₂O-0.1% TFA, solvent B 90% MeOH-10% H₂O-0.1% TFA, gradient0-100% B, 12 minutes). The desired fractions were concentrated to removemost of the MeOH, neutralized by saturated NaHCO₃ to pH 10 and extractedwith EtOAc (2×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo to give 38 mg (yield: 93%) of 260G as a solid.Mass (M+H)⁺=544.

A solution of 260G (38 mg, 0.070 mmol) in MeOH (2 mL) at roomtemperature was treated with 5% Pd/C (10 mg). The reaction mixture wasstirred under a hydrogen atmosphere for 16 hours. The catalyst wasremoved by filtration. The filtrate was concentrated in vacuo to give 25mg (yield: 87%) of Compound 260 as a solid. It had an analytic HPLCretention time=1.71 min (Phenomenex Su C18 4.6×50 mm column 10-90%aqueous methanol containing 0.2% H₃PO₄, 4 min grad. monitored at 220nm). Mass [M+H]⁺=410.

EXAMPLE 261((3R,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]-triazin-5-yl)methyl)-4-((R)-1-phenylethylamino)piperidin-3-yl)methanol

261A. Preparationof(3R,4R)-1-(tert-butoxycarbonyl)-4-((R)-1-phenylethylamino)-piperidine-3-carboxylicacid

A mixture of 252D (460 mg, 1.22 mmol) and NaOEt (1.25 mL, 21% wt inEtOH) in EtOH (10 ml) was stirred at 50° C. for 3 hrs, then at RT forabout 48 hours. The reaction mixture was concentrated in vacuo, followedby the addition of water. The mixture was acidified with 1N HCl to pH4-5 and the solid was collected by filtration, washed with water anddried to give 300 mg (yield: 71%) of 252A. It had an analytical HPLCretention time=2.065 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90%aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at220 nm). Mass (M+1)⁺=349.

261B. Preparation of (3R,4R)-1-tert-butyl 3-methyl4-((R)-1-phenylethylamino)-piperidine-1,3-dicarboxylate

To a solution of 261A (280 mg, 0.80 mmol) in 6 mL of 1:1 CH₂Cl₂/MeOH wasadded a solution of TMSCHN₂ (0.82 ml, 1.64 mmol, 2N in hexane). Themixture was stirred at room temperature for 30 min, then concentrated invacuo and purified by flash chromatography (hexane/EtOAc: 80:20) onsilica gel to give Compound 261B as an oil. It had an analytical HPLCretention time=2.187 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90%aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at220 nm). Mass (M+1)⁺=363.

261C. Preparation of((3R,4R)-4-((R)-1-phenylethylamino)piperidin-3-yl)methanol

To a solution of 261B (270 mg, 0.75 mmol) was added LiBH₄ (15.5 mg, 0.71mmol). The mixture was heated to reflux for 1.0 hr. HPLC showed stillsome starting material remaining. More LiBH₄ (15.5 mg, 0.71 mmol) wasadded, and the mixture was heated for another 2.0 hrs. After cooling toroom temperature, ice water was added, and the mixture was concentratedin vacuo to remove the THF. The aqueous residue was extracted with EtOAc(×3) and the combined extracts were dried (Na₂SO₄), and concentrated invacuo. The residue was taken into 2 mL of CH₂Cl₂ and 2 mL of TFA wasadded. The mixture was stirred at room temperature for 30 min. Themixture was concentrated in vacuo, followed by drying under high vacuumovernight to afford 261C as an oil. It had an analytical HPLC retentiontime=0.590 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueousmethanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm)and a LC/MS M⁺+1=235. This material was used directly in the nextreaction step without further purification.

261D. Preparation of((3R,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]-triazin-5-yl)methyl)-4-((R)-1-phenylethylamino)piperidin-3-yl)methanol

Compound 261D was prepared from 261C in a similar process as used forCompound 146E. It had an analytical HPLC retention time=1.761 min.(Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueous methanolcontaining 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm) and aLC/MS M⁺+1=487.

A mixture of 261D (160 mg, 0.33 mmol), 10% Pd/C (39 mg) and ammoniumformate (166 mg, 2.63 mmol) in MeOH (15 ml) was heated to reflux for 1.0hr. After cooling to room temperature, the catalyst was removed byfiltration and the filtrate was concentrated in vacuo. The residue wasdissolved in water, basified with aqueous NaHCO₃ and extracted withEtOAc (3×). The combined extracts were dried (Na₂SO₄) and concentratedin vacuo to give 64 mg (yield: 51%) of Compound 261 as a solid (64 mg,51%). It had an analytical HPLC retention time=1.137 min. (ChromolithSpeedROD column 4.5×50 mm, 10-90% aqueous methanol containing 0.1% TFAover 4 min, 4 mL/min, monitoring at 220 nm) and a LC/MS M⁺+1=383.

EXAMPLE 262rac-(3R,4R)-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidine-3,4-diamine

262A. Preparation of (3R,4R)-tert-butyl4-(benzyloxycarbonyl)-3-hydroxypiperidine-1-carboxylate

To a stirred mixture of Compound 249A (1.40 g, 6.47 mmoL) in 10 mL ofCH₂Cl₂ was added Et₃N (1.08 mL, 7.76 mmoL), followed by Cbz-OSu (1.69 g,6.80 mmoL). The reaction mixture was stirred at room temperature for 16hrs and then diluted with 300 mL of EtOAc. The organic layer was washedwith 5% citric acid solution (2×40 mL), 5% K₂CO₃ solution (2×40 mL) andbrine (40 mL) and dried (MgSO₄). The residue was filtered andconcentrated in vacuo to afford 2.25 g (yield: 99%) of Compound 262A. Ithad an analytical HPLC retention time=3.02 min. (Phenomenox S5 C18-HC4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1%TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=351.

262B/C. Preparation of (3R,4R)-tert-butyl 3-azido-4-(benzyloxycarbonyl)piperidine-1-carboxylate

To a stirred solution of Compound 262A (2.23 g, 6.36 mmoL) and Et₃N(1.20 mL, 0.83 mmoL) in 30 mL of CH₂Cl₂ under nitrogen at 0° C. wasadded and methanesulfonyl chloride (0.49 mL, 6.36 mmoL) over 5 min. Themixture was stirred at 0° C. for 35 min and then diluted with 40 mL ofCH₂Cl₂. The mixture was washed with water (2×25 mL), brine (20 mL) anddried (MgSO₄). The mixture was filtered and concentrated in vacuo toafford the crude mesylate. To the mesylate in 20 mL of DMSO was addedNaN₃ (1.65 g, 25.5 mmoL). The mixture was heated at 90° C. for 17 h andcooled to room temperature. The mixture was diluted with 200 mL of EtOAcand washed with water (4×200 mL), saturated NaHCO₃ solution (40 mL),brine (40 mL) and dried (MgSO₄). Filtration, concentration in vacuo,followed by flash chromatography (15-50% EtOAc in hexane) on silica gelgave 696 mg (29%) of 262B (DiastereomerA, Rf=0.65) and 262C(DiastereomerB, Rf=0.70). 262B had an analytical HPLC retentiontime=3.51 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+1=376. 262C had an analytical HPLC retentiontime=3.51 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+1=376.

262D. Preparation of benzyl(3R,4R)-3-azido-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidin-4-ylcarbamate

Compound 262D was prepared from Compound 262B in a similar process asdescribed for Compound 247A. It had an analytical HPLC retentiontime=2.96 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+1=528.

Compound 262 was prepared from Compound 262D in a similar process asdescribed for Compound 249A. It had an analytical HPLC retentiontime=1.27 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+1=368.

EXAMPLE 263rac-N-[(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]urea

263A. Preparation of benzyl(3R,4R)-3-amino-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)piperidin-4-ylcarbamate(Chiral, Diastereomer A)

Compound 263A was prepared from Compound 262C in a similar process asdescribed as used for Compound 146E. It had an analytical HPLC retentiontime=2.71 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+1=502.

263B. Preparation of benzyl(3R,4R)-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-3-ureidopiperidin-4-ylcarbamate

To a stirred mixture of Compound 263A (77.0 mg, 0.15 mmoL) in 2 mL ofCH₂Cl₂ at 0° C. was added trichloroacetylisocyanate (28.9 mg, 0.18mmoL). The mixture was stirred at 0° C. for 30 min, and 1 mL of methanolwas added. This mixture was then concentrated in vacuo to give a crudeoil. This crude material was dissolved in 3 mL of methanol and 2 mL of20% K₂CO₃ solution was added. The mixture was stirred at roomtemperature for 2 h, then diluted with 10 mL of water. It wasconcentrated in vacuo to remove methanol and then extracted with EtOAc(3×15 mL). The combined EtOAc extracts were washed with brine (10 mL)and dried (MgSO₄). Filtration followed by concentration in vacuoafforded 70 mg (yield: 84%) of Compound 263B. It had an analytical HPLCretention time=2.51 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min,monitoring at 220 nm) and a LC/MS M⁺+1=545.

Compound 263 was prepared from Cmpound 263B in a similar way asdescribed for compound 249A. It had an analytical HPLC retentiontime=1.32 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+1=411.

EXAMPLE 264rac-N-[(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]methanesulfonamide

264A. Preparation of benzyl 7-(methylsulfonyl)-3,7-diaza-bicyclo[4.1.0]heptane-3-carboxylate (racemic)

To a stirred mixture of benzyl3,7-diaza-bicyclo[4.1.0]heptane-3-carboxylate (410 mg, 1.77 mmol.,prepared as shown in Tetrahedron Letters, 43(23), 4289-4293, 2002) in 5mL of CH₂Cl₂ was added triethylamine (0.74 mL, 5.31 mmoL), followed bymethanesulfonyl chloride (0.18 mL, 2.30 mmoL). The mixture was stirredat room temperature for 2.5 h and then diluted with 120 mL of EtOAc.This mixture was washed with 5% citric acid solution (3×30 mL),saturated NaHCO₃ solution (30 mL), and brine (30 mL). The organic layerwas dried (MgSO₄), filtered and concentrated in vacuo to give Compound264A in quantitative yield. It had an analytical HPLC retentiontime=2.56 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueousmethanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220nm) and a LC/MS M⁺+Na=333.

264B. Preparation of (3R,4R)-rel-benzyl4-azido-3-(methylsulfonamido)piperidine-1-carboxylate

To a stirred mixture of compound 264A (549 mg, 1.77 mmoL) in 4 mL ofDMSO was added NaN₃ (458 mg, 7.08 mmoL). The mixture was stirred at roomtemperature for 2 h, and diluted with 80 mL of EtOAc. The mixture waswashed with water (3×100 mL), saturated NaHCO₃ solution (40 mL), andbrine (40 mL). The EtOAc layer was dried (MgSO₄), filtered andconcentrated in vacuo to give 530 mg (yield: 85%) of Compound 264B. Ithad an analytical HPLC retention time=2.90 min. (Phenomenox S5 C18-HC4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1%TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=354.

264C. Preparation of (3R,4R)-rel-benzyl4-amino-3-(methylsulfonamido)piperidine-1-carboxylate

To a stirred mixture of Compound 264B (530 mg, 1.50 mmoL) in 6 mL of THFand 1 mL of water was added Ph₃P (900 mg, 3.43 mmoL). The reactionmixture was heated at 70° C. for 15 h and cooled to room temperature.This mixture was concentrated in vacuo, diluted with 15 mL of 2N HClsolution, and then washed with CHCl₃ (3×20 mL). The aqueous was basifiedto pH 12 by the addition of 50% NaOH solution, saturated with NaCl, andthen extracted with EtOAc (3×25 mL). The combined EtOAc extracts werewashed with brine (15 mL), dried (MgSO₄), filtered and concentrated invacuo to give 490 mg (yield: 100%) of Compound 264C. It had ananalytical HPLC retention time=1.67 min. (Phenomenox S5 C18-HC 4.6×50 mmcolumn, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=328.

264D. Preparation of tert-butyl(3R,4R)-rel-1-((4-(3-methoxyphenylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)methyl)-3-(methylsulfonamido)piperidin-4-ylcarbamate

To a stirred solution of compound 264C (490 mg, 1.50 mmoL) in 6 mL ofCH₂Cl₂ was added Et₃N (0.63 mL, 4.50 mmoL), followed by di-t-butyldicarbonate (390 mg, 1.80 mmoL). The reaction mixture was stirred atroom temperature for 3 h. The mixture was diluted with 60 mL of EtOAc,washed with saturated NaHCO₃ solution (2×15 mL) and brine (15 mL). Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuo togive a crude intermediate. The crude intermediate was purified by flashchromatography (hexane-EtOAc) on silica gel to give 131 mg of puremeterial. To this intermediate in 6 mL of methanol under nitrogen wasadded 20% Pd(OH)₂/C (30 mg). The reaction mixture was purged withhydrogen several times and stirred under hydrogen atmosphere for 18 h.The catalyst was removed by filtration using a 4 μM polycarbonate filmand rinsed with MeOH (4×10 mL). The combined filtrates were concentratedin vacuo to give 89 mg of crude amine intermediate.

Compound 264D was prepared from this intermediate in a similar processas described for 146E. It had an analytical HPLC retention time=2.72min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanolover 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) anda LC/MS M⁺+1=546.

To a stirred solution of compound 264D (120 mg, 0.22 mmoL) in 3 mL ofCH₂Cl₂ was added TFA (2.5 mL, 32.4 mmoL). The mixture was stirred atroom temperature for 40 min, concentrated in vacuo, and purified by aprep HPLC to give 71 mg (yield: 73%) of Compound 264. It had ananalytical HPLC retention time=1.54 min. (Phenomenox S5 C18-HC 4.6×50 mmcolumn, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=446.

EXAMPLE 265N-[(3S,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]methanesulfonamide

Preparation of Compound 265A

Compound 265A was prepared from compound 262C (chiral, regioisomer B) ina similar way as described for compound 262D. It had an analytical HPLCretention time=2.73 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90%aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min,monitoring at 220 nm) and a LC/MS M⁺+1=502.

Preparation of Compound 265B

To a stirred mixture of compound 265A (60.0 mg, 0.12 mmoL) and Et₃N(0.05 mL, 0.36 mmoL) in 4 mL of DCM was added methanesulfonyl chloride(15.0 mg, 0.13 mmoL). This reaction mixture was stirred at roomtemperature for 20 h and then diluted with 100 mL of EtOAc. The mixturewas washed with saturated NaHCO₃ solution (20 mL) and brine (20 mL). TheEtOAc layer was dried (MgSO₄), filtered and concentrated in vacuo togive 70 mg of compound 265B in a quantitative yield. Compound 265B hasan analytical HPLC retention time=2.61 min. (Phenomenox S5 C18-HC 4.6×50mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4ml/min, monitoring at 220 nm) and a LC/MS M⁺+1=580.

Compound 265 was prepared from compound 265B (chiral, regioisomer B) ina similar way as described for Compound 249A. The structure of Compound265 was assigned based on comparison of ¹H-NMR from that of Compound264. The compound had an analytical HPLC retention time=1.50 min.(Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MSM⁺+1=446.

EXAMPLE 266N-[(3R,4R)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]methanesulfonamide(Enantiomer A)

Compound 266 was obtained from 264 by a chrial preparative HPLCseparation as the first eluted peak with >99% ee. Compound 127A an HPLCretention time=6.3 min (Chiral Pak, AD 250×4.6 mm column, 10 micron, 220nM, 0.8 mL/min, EtOH as eluant). LC/MS M⁺+1=446.

EXAMPLE 267N-[(3S,4S)-4-amino-1-({4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl}methyl)piperidin-3-yl]methanesulfonamide(Enantiomer B)

Compound 267 was obtained from 264 by a chiral preparative HPLCseparation as the second eluted peak with >99% ee. Compound 267 had anHPLC retention time=7.9 min (Chiral Pak, AD 250×4.6 mm column, 10micron, 220 nM, 0.8 mL/min, EtOH as eluant). LC/MS M⁺+1=446.

1. A compound of formula I

wherein R¹ is cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl; R² is aryl, substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl; R³ is hydrogen, alkyl or substituted alkyl; X is a direct bond, —NR³— or —O—; Y is a direct bond, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl; or a pharmaceutically acceptable salt or stereoisomer thereof, with the proviso that R² is not indazolyl or substituted indazolyl.
 2. A compound of the formula

wherein X is a direct bond, —NR³— or —O—; Z is

R² is aryl or substituted aryl, heteroaryl or substituted heteroaryl, R³, R⁴ and R⁵ are independently selected from hydrogen, alkyl and substituted alkyl; R⁶, R^(6a) and R^(6b) are independently selected from the group consisting of one or more hydrogen, halogen, alkyl, alkoxy, aryloxy, —CN, —NH₂, —OH, —COOH, —CH₂OR⁵, —CONHSO₂R⁵, —CONR⁴R⁵, —NHalkyl, —NHCOalkyl, —NR⁴SO₂alkyl, —NR⁴SO₂NR⁴R⁵, —OCONR⁴R⁵, —CF₃ and —OCF₃, two of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable; R⁷ is hydrogen, alkyl or —NH₂, and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or stereoisomer thereof.
 3. A compound of the formula

wherein X is a direct bond, —NR³— or —O—; R² is aryl or substituted aryl, heteroaryl or substituted heteroaryl, R³, R⁴ and R⁵ are independently selected from hydrogen, alkyl and substituted alkyl; R⁶, R^(6a) and R^(6b) are independently selected from the group consisting of one or more hydrogen, halogen, alkyl, alkoxy, aryloxy, —CN, —NH₂, —OH, —COOH, —CH₂OR⁵, —CONHSO₂R⁵, —CONR⁴R⁵, —NHalkyl, —NHCOalkyl, —NR⁴SO₂alkyl, —NR⁴SO₂NR⁴R⁵, —OCONR⁴R⁵, —CF₃ and —OCF₃, two of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or stereoisomer thereof.
 4. The compound according to claim 3 wherein R² is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, oxazole, substituted oxazole, thiazole, substituted thiazole, pyrazinyl or substituted pyrazinyl; R⁶, R^(6a) and R^(6b) are independently selected from the group consisting of one or more hydrogen, —NH₂, OH, alkoxy, —CONR⁴R⁵, —NR⁴SO₂alkyl, —NR⁴SO₂NR⁴R⁵, —OCONR⁴R⁵, —NHalkyl and —NHCOalkyl; X is —NH—; and n is 1 or
 2. 5. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.
 6. A pharmaceutical composition comprising one or more compounds of claim 2 and a pharmaceutically acceptable carrier.
 7. A pharmaceutical composition comprising one or more compounds of claim 3 and a pharmaceutically acceptable carrier.
 8. A pharmaceutical composition comprising one or more compounds according to claim 1 in combination with a pharmaceutically acceptable carrier and one or more other anti-cancer or cytotoxic agent.
 9. The pharmaceutical composition according to claim 8 wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, trastuzumab, erlotinib, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridol, bortezomib and biological response modifiers.
 10. A method for treating a proliferative disease, comprising administering to a mammalian species in need thereof, a therapeutically effective amount of one or more compound according to claim
 1. 11. The method of claim 10 wherein the proliferative disease is selected from the group consisting of cancer, psoriasis and rheumatoid arthritis.
 12. The method of claim 11 wherein the proliferative disease is cancer.
 13. The method of claim 12 further comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of one or more other anti-cancer or cytotoxic agent in combination with one or more compound according to claim
 1. 14. The method of claim 13 wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, trastuzumab, erlotinib, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols, proteasome inhibitors including bortezomib and biological response modifiers.
 15. A method of modulating receptor tyrosine kinase activity which comprises administering to a mammalian species in need thereof, an effective amount of one or more compound according to claim
 1. 16. The method of claim 15 wherein said receptor tyrosine kinase is selected from the group consisting of HER1, HER2 and HER4.
 17. A method for treating diseases associated with signal transduction pathways operating through growth factor receptors, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of one or more compound according to claim
 1. 18. A method for identifying kinase ATP-competitive inhibitors which comprises selecting a compound as defined in claim 1, that binds in the adenine pocket, the ribose pocket, the phosphate binding pocket, specificity region 1 and specificity region 2 of the kinase as shown in FIG. 2, wherein the group occupying the ribose and/or the phosphate binding pocket can interact with one or more of the absolutely conserved residues involved in phosphate binding.
 19. The method according to claim 18 wherein the group interacts with residues Asn818 and/or Asp 831 (HER1 numbering) or the correponding residues in a different kinase of the ribose/phosphate binding pockets.
 20. A compound having the formula

or a pharmaceutically acceptable salt thereof.
 21. A pharmaceutical composition comprising the compound according to claim 20 and a pharmaceutically acceptable carrier. 